PROPOSAL FOR THE INCLUSION OF ARTESUNATE and … · 3. Name of the organisation(s) consulted and/or supporting the application Médecins Sans Frontières (MSF) Medicines for Malaria

WHO 19th Expert Committee on the Selection and use of Essential Medicines DNDi November 2012

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PROPOSAL FOR THE INCLUSION OF

ARTESUNATE and MEFLOQUINE (ASMQ)

Fixed Dose Combination (FDC) TABLETS 25 / 55 mg and 100 / 220 mg

AS A TREATMENT FOR UNCOMPLICATED FALCIPARUM MALARIA IN THE WHO MODEL LIST OF ESSENTIAL MEDICINES

Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland

Person to contact:

Dr. Jean René Kiechel Drugs for Neglected Diseases initiative (DNDi) 15 Chemin Louis-Dunant 1202 Geneva Switzerland Tel: +41 (0)22 906 9230 Fax: +41 (0)22 906 9231 Email: [email protected]


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Table of Contents

WHO Model List Application Abbreviations………………………………………………………………………………………….……………………….4 Synopsis……………………………………………….…………………………………………………………………………6 1. Summary statement of the proposal for inclusion…………………………………………………………….6 2. Name of the focal point in WHO for this application…………………………………..…………………….6 3. Name of the organisation(s) consulted and/or supporting the application………………………….6 4. International Nonproprietary Name (INN, generic name) of the medicine……………………….….6 5. Formulation proposed for inclusion…………………..……...………………………………......................7 6. International availability……………………………………………………………….……………………………….7 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group………………………………………………………………………………………………………………………………7 8. Information supporting the public health relevance………………………………………………………….7

8.1 Disease burden – Epidemiological information……………………………………………….……9 8.2 Assessment of current use and target population……………….……………………..…….….9

9. Treatment details: 9.1 Dosage regimen, duration………………....…………………………………………….……………….11 9.2 Reference to existing WHO and other clinical guidelines……………………………………….12 9.3 Need for special diagnostic or treatment or monitoring facilities and skills..…………….13

10. Summary of comparative efficacy: 10.1 Identification of clinical evidence ……………..………………………….……………………….….13 10.2 Summary of available data ……………………………………………………………………….……..13 10.3 Summary of available estimates of comparative efficacy……………....…………………….14 10.4 Critical elements in the ASMQ FDC development program......................................16

11. Summary of comparative evidence on safety: 11.1 Estimate of total patient exposure to date….……………………………………………………..19 11.2 Description of adverse effects/reactions………………....…………………………………………20 11.3 Summary of Product Characteristics…………………………………………………………..……..26 11.4 Summary of comparative safety against comparators…………………………...…………...33

12. Summary of available data on comparative cost and cost effectiveness within the


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pharmacological class or therapeutic group……………………………………………………………………….39 13. Summary of regulatory status of medicines……………...………………………………………..……….39 14. Availability of pharmacopoeial standards.………………………………………….......................……40 15. Proposed text for WHO Model Formulary……………………………….…….……………………………..40 Appendix………………….…………………………………………………………………………..…………………….…41 References……………….…………………………………………………………………………………………..…….….56


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Abbreviations

ACTs Artemisinin-based Combination Therapies AEs Adverse Events AL Artemether-Lumefantrine FDC AOR Age-adjusted Odds Ratio AQ+SP Amodiaquine plus Sulphadoxine-Pyrimethamine AS Artesunate AS+AQ Artesunate plus Amodiaquine ASMQ FDC Artesunate- Mefloquine Fixed Dose Combination AS+MQ Artesunate plus Mefloquine AS-Pyr Artesunate-Pyronaridine FDC AS+SP Artesunate plus Sulphadoxine-Pyrimethamine AUC Area under the Concentration time-curve API Active Pharmaceutical Ingredient CI Confidence interval Cmax Maximum plasma concentration CQ+SP Chloroquine plus Sulphadoxine-Pyrimethamine CSF Cerebrospinal fluid DHA-PQ Dihydroartemisinin-Piperaquine FDC D1…D63 Day 1…day 63 DHA-TP Dihydroartemisinin-Trymetoprim DNDi Drugs for Neglected Diseases initiative ECG Electrocardiogram EDCTP European & Developing Countries Clinical Trials Partnership EML Essential Medicines List FACT Fixed-dose Artesunate-based Combination Therapies Project FDC Fixed Dose Combination GPARC WHO Global Plan for Artemisinin Resistance Containment Hcl Hydrochloride IRRMH Incidence Rate Ratio, Using Mantel-Haenszel method (statified by categories) mFLT Multi-first-line treatment MMV Medicines for Malaria Venture MSF Médecins Sans Frontières MQ Mefloquine M888 Mefloquine 8mg/kg per day over 3 days MAS3 Combination of 25 mg/kg of Mefloquine and 12 mg/kg of Artesunate given over 3 days NMCP National Malaria Control Program ORS Oral rehydration salt PCR Polymerase Chain Reaction PI Principal Investigator


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PK Pharmacokinetic PSI Population Services International PV Pharmacovigilance RDT Rapid Diagnostic Test SAE Serious adverse events SD Single dose SPC Summary of Product Characteristics Tb Tablets TDR WHO Special Programme for Research and Training in Tropical Diseases TEAEs Treatment emergent adverse event UV Ultra violet WBC White blood cells count WHO World Health Organization WPW Wolf Parkinson White WWARN Worldwide Antimalarial Resistance Network


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Synopsis

1. Summary statement of the proposal for inclusion

Artesunate (AS) and mefloquine (MQ) Fixed Dose Combination (FDC) tablets 25 / 55 mg and 100 / 220 mg is proposed for inclusion in the World Health Organization (WHO) Model List of Essential Medicines, section 6.5.3.1, as an alternative treatment for patients with uncomplicated falciparum malaria.

2. Name of the focal point in WHO for this application

Dr Peter Olumese Medical Officer (Treatment Guidelines & Policy) Diagnosis, Treatment and Vaccines Team Global Malaria Programme

Tel. direct: +41 22 791 4424 Fax direct: +41 22 791 4824 Mobile: +41 79 218 9806 E-mail: [email protected] Website: http://www.who.int/malaria 3. Name of the organisation(s) consulted and/or supporting the application

Médecins Sans Frontières (MSF) Medicines for Malaria Venture (MMV)

4. International Nonproprietary Name (INN, generic name) of the medicine

Artesunate and mefloquine Fixed Dose Combination tablets Artesunate: CAS Reg. No. 88495-63-0 Mefloquine hydrochloride: CAS reg No. 51773-92-3


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5. Formulation proposed for inclusion

Artesunate and mefloquine hydrochloride Fixed Dose Combination tablets 25 / 55 mg and Artesunate and mefloquine hydrochloride Fixed Dose Combination tablets 100 / 220 mg 6. International availability

Artesunate and mefloquine Fixed Dose Combination tablets is available under the brand name of Farmanguinhos Artesunato + Mefloquina 25 / 55 mg and Farmanguinhos Artesunato + Mefloquina 100 / 220 mg.1 Artesunate and mefloquine Fixed Dose Combination tablets is also available at Cipla under the brand name of Artesunate 25 mg + Mefloquine 55 mg and Artesunate 100 mg + Mefloquine 220 mg.2 Manufactured in Brazil by: FARMANGUINHOS Av. Comandante Guaranys, 447 – Jacarepaguá Rio de Janeiro – RJ - Brazil CNPJ: 33.781.055/0049-80 Manufactured in India by: CIPLA Ltd. Mumbai Central Mumbai 400 008 Maharashtra India

7. Whether listing is requested as an individual medicine or as an example of a therapeutic group

It is requested that artesunate (already listed in section 6.5.3.1 as an essential medicine for the treatment of P. falciparum malaria cases) be listed for the use as a fixed dose combination therapy with mefloquine, another WHO EML-listed medicine (mefloquine, also listed in section 6.5.3.1 as an essential medicine for the treatment of P. falciparum malaria cases).

8. Information supporting the public health relevance

The World Health Organization (WHO) regards both artesunate (AS) and mefloquine (MQ) as Essential Medicines for the treatment of malaria3; and since 20014 the combination of AS+MQ has been one of the WHO-recommended ACTs for first-line antimalarial treatment.5 Despite its efficacy, the non-fixed combination poses problems regarding patient compliance and thus development of resistance. FDCs have been identified by experts gathered by WHO (clinical, regulatory, intellectual property and production) as highly desirable in terms of adherence and ease of treatment, containment of resistance, reducing diversions and possibly reducing costs.6 A WHO guideline for registration of medicinal products has amplified in 2005 the support for the development of fixed-dose combinations to treat P. falciparum, from a public health perspective.7


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More recently, within the landscape of artemisinin resistance malaria in the Greater Mekong Sub region, the WHO Global Plan for Artemisinin Resistance Containment (GPARC) encourages the manufacture and use of fixed-dose combinations and recommends providing preferential funding for such formulations in areas where the recommended treatment is available as a fixed-dose combination.8 As reported in 2011, 84 of 87 P. falciparum malaria-endemic countries and territories use ACTs as national policy for the 1st line treatment of falciparum malaria with varying levels of coverage.9 The combination of AS+MQ is national policy10 for first-line treatment of uncomplicated malaria in Cambodia and Malaysia in the Western Pacific region and in Thailand and Myanmar in South East Asia, while in Vietnam AS+MQ is recommended as rescue treatment. In the Americas region, Peru, Venezuela, Bolivia and Brazil11 adopted AS+MQ for treating uncomplicated malaria and in Nicaragua AS+MQ is recommended as second line treatment. Depending on the degree of parasite resistance to MQ, ASMQ FDC may also be useful in additional countries in Asia, in Latin America as well as for African patients.12

Following the idea that antimalarial drug resistance could be prevented by combining structurally unrelated antimalarial agents,13-14 different regimens of mefloquine with artesunate were tested and proved their efficacy and safety in Bangkok and in Karen refugee camps in Tak province of Thailand.15-16 In camps for displaced persons located along the Thai-Myanmar border, combined mefloquine and artesunate therapy has been evaluated since 199117 and the combination of 25 mg/kg of mefloquine and 12 mg/kg of artesunate given over 3 days (MAS3) was deployed as first-line treatment. The strategy of artemisinin-based combination therapy with mefloquine was developed and adopted in Thailand in 1994 where treatment of uncomplicated malaria has been modified several times during the past 30 years to counter the rapid emergence and spread of drug resistance.17The deployment of the combination has led to a reduction in incidence of falciparum malaria and has been associated with a halt of mefloquine resistance.18 Based on very large studies that confirmed its safety and efficacy19 and through continuous parasitological efficacy monitoring20 MAS3 has remained the treatment of choice since in this area.21 Over the subsequent 17 years of continuous MAS3 deployment, the cure rates assessed at day-42 remained above 90%.22 Artesunate (AS) and mefloquine (MQ) are well-established drugs for the treatment of P. falciparum malaria. Their co-administration as loose tablets combination has been in use for many years and efficacy data when used in both adults and children is largely available from Asia but also from other geographical areas such as Latin America and Africa. In line with recommendations provided by WHO and malaria experts in 20014 and acting in the public interest, artesunate and mefloquine Fixed Dose Combination (ASMQ FDC) tablets were developed by the FACT Project (the Fixed-dose artesunate-based Combination Therapies Project), a consortium of several public sector research and development teams, as well as clinical research organizations from Europe, Asia, Africa and Latin America, under the coordination of DNDi and TDR.23 Additional Public Health benefits of ASMQ FDC, towards supporting ACT’s effectiveness are:

� The Age-based unit dose packaging appropriate for all age groups, paediatric friendly formulations; ease of dosing at all levels of the health care system, including use in the community and private sectors.

� Co-formulation of the drugs reduces the pill burden and, more importantly, eliminates the possibility of patients taking only one component of the combination or, of providers selling only one drug to reduce costs.24

� Fewer tablets to take for patients of all ages [both active drugs are taken together], once per day over three days, the drug regimen is easy to understand and user-friendly, and there is no need to time the doses with food.


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8.1 Disease burden – epidemiological information

According to a recent published study25 that compiled information on the number of cases reported by National Malaria Control Programs in 99 countries and combining various estimates for all areas of transmission, a total of worldwide malaria cases in 2009 were estimated as 225 million. The majority of cases (78%=176 million) were in the WHO African region, followed by Southeast Asia (15%=34 million) and the Eastern Mediterranean regions (5%= 12million). Sixteen countries accounted for 80% of all estimated cases globally, all of them in the African region except for India and Myanmar. Estimates of clinical burden are also summarized for each country and for each of the WHO global regions as follows:

8.2 Assessment of current use

Scientific evidence supporting the development of ASMQ FDC derives from the well-established use of their combined administration demonstrated by studies in which these drugs have been administrated as different regimens, in non-fixed combination or as co-blister formulations. Artesunate (AS) and mefloquine (MQ) co-administered as loose tablets combination has been in use for many years. As shown in the table below, clinical data is reported from more ~14000 patients treated with AS+MQ as loose tablets combination in more than 90 open and randomized clinical trials conducted in 22 countries from 3 continents since 1992: See in Appendix 1, the references for clinical data on the use of artesunate (AS) and mefloquine (MQ) co-administration as loose tablets and as fixed-dose combination.

HHaayy SSII,, OOkkiirroo EEAA,, GGeetthhiinngg PPWW,, PPaattiill AAPP,, TTaatteemm AAJJ,, eett aall.. ((22001100)) EEssttiimmaattiinngg tthhee GGlloobbaall CClliinniiccaall BBuurrddeenn ooff PPllaassmmooddiiuumm ffaallcciippaarruumm MMaallaarriiaa iinn 22000077.. PPLLooSS MMeedd 77((66)):: ee11000000229900.. ddooii::1100..11337711//jjoouurrnnaall..ppmmeedd..11000000229900


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Continent Countries Number of

studies

Number of

patients

Total

patients

per

continent

Year of studies Year of

publication

South East Asia Thailand, ASMQ FDC N=275 31 7.627 9.337 1992-2011 1995-2012

Myanmar, ASMQ FDC N=169 4 1.467 1998-2009 2004-2010

India 3 122 2001-2008 2006-2012

Bangladesh 1 121 2003 2005

Western Pacific Cambodia 19 1.419 2.294 2001-2008 2006-2012

Laos 4 368 2002-2007 2004-2010

Vietnam 3 507 1997-2008 2004-2012

Latin America Peru 5 598 24.766 2000-2006 2003-2011

Bolivia 1 70 2001 2004

Ecuador 1 100 Not Available 2003

Colombia 2 153 2006-2008 2010-2012

Brazil, ASMQ FDC N=23.845 1 23.845 2006-2008 2012

Africa Senegal 2 299 1.968 2003-2008 2007-2010

Mali 1 232 2004-2005 2008

Gabon 2 92 2005-2006 2007-2010

Nigeria 3 619 1994-2008 1998-2009

Sudan 2 68 2000-2003 2003-2005

Cameroon 2 274 2006-2009 2010

Kenya 1 129 2004 2006

Côte d’Ivoire 1 75 2007 2011

Cameroon, Benin & Côte D’Ivoire

1 104 2001 2002

Burkina Faso, Tanzania & Côte d’Ivoire

1 76 2007-2008 2012

22 countries 91 studies 38.315 patients From 1992 to 2011 From 1995 to 2012


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8.3 Assessment of target population

According to WHO,9 it is estimated that more than 1.2 million malaria cases occurred in the nine countries (Brazil, Bolivia, Cambodia, Colombia, Malaysia, Myanmar, Peru, Thailand and Venezuela) where AS+MQ is part of the national malaria protocol for the treatment of uncomplicated malaria. In addition, depending of the resistance profile of the country and the national strategy adopted towards reducing drug pressure, ASMQ FDC may also be useful in other countries in Asia, Latin America and Africa. The population at risk in the 106 countries and territories classified as endemic for malaria are potential beneficiaries targeted in the strategy “from control to elimination” of malaria. About half the world’s population (3.3 billion) lives in areas that have some risk of malaria transmission and one fifth (1.2 billion) live in areas with a high risk of malaria. Another 2.1 billion live in areas of low risk. The largest populations at any risk of malaria are found in South-East Asia and the Western Pacific regions. Africa has the largest number of people living in areas with a high risk of malaria, followed by South-East Asia Region. As reported in 20119 approximately 86% of global malaria deaths were among children less than five years of age, most of which (91%) in sub-Saharan Africa. With specific presentations for children of ages between 6 months and 11 years, ASMQ FDC addresses the needs of children, the primary victims of malaria worldwide. The ACT Cochrane review published in 200912 which compared 50 studies using either AS+MQ, AL, DHA-PQ, AS+AQ, AS+SP or AQ+SP, concludes that in the absence of mefloquine resistance, AS+MQ is likely to be highly effective in African countries. According to WHO-2010 malaria guideline, the main reason for restricting the use of AS+MQ in African children so far has been excessive vomiting associated with mefloquine at the recommended dose of 25 mg/kg. Based on published data,26 WHO recommended5 reconsidering AS+MQ in Africa, with specific concerns regarding toxicity/vomiting in children. To provide additional information DNDi is sponsoring a multicentre, open-label, prospective, randomised, controlled, Phase IV study in Africa, to assess efficacy, safety and pharmacokinetics of ASMQ FDC in ~1000 children with uncomplicated P. falciparum malaria from Tanzania, Burkina Faso and Kenya versus artemether-lumefantrine.27 ASMQ FDC could play a role within the strategy of multiple first-line therapies (mFTs); the gametocytocidal effects of the artemisinin derivative and the prophylactic effect of a longer-acting partner drug [both active drugs taken together] are predicted to have the greatest impact on transmission across all areas in the short-term time scale of one of the published models.28 Deployment of mFTs is proposed as one of the strategies to reduce drug pressure on the parasite pool.29 If these models are to be followed, the question on where and how ASMQ FDC should be deployed within the landscape of several quality- assured ACTs available in the market and promising antimalarials currently in the pipeline remains open,30 together with pragmatic strategies as the recently piloted AMFm-Phase I.31

9. Treatment details:

9.1 Dosage regimen, duration

The suggested regimen is: Recommended Dosage for ASMQ FDC tablets

Weight (Kg) Age Recommended Dose 5 - 8 6-11 months One ASMQ FDC Tablet 25 / 55 mg1 daily for 3 days 9 -17 1 – 6 years Two ASMQ FDC Tablets 25 / 55 mg1 daily for 3 days 18 - 29 7 – 12 years One ASMQ FDC Tablet 100 / 220 mg2 daily for 3 days ≥ 30 ≥ 13 years Two ASMQ FDC Tablets 100 / 220 mg2 daily for 3 days

1 Mefloquine HCl 55 mg are equivalent to 50 mg of mefloquine 2 Mefloquine HCl 220 mg are equivalent to 200 mg of mefloquine


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Dosing of ASMQ FDC tablets is based on four age-weight categories. The recommended daily dose for each category is a best approximation of the target dose for each drug: 4 mg/kg for artesunate and 8 mg/kg for mefloquine, corresponding to total doses of 12 mg/kg and 24 mg/kg, respectively.

Dose AS MQ HCl Base of MQ

Min dose mg/kg/dose/day

Max dose mg/kg/dose/day





WHO recommendations

2 10 7 11

ASMQ FDC

6-11 months (5-8kg)

1x 25/551 mg Tablet => 25 mg AS and 50mg base

of mefloquine

3.1 5 6.8 11 6.2 10

1-6 yrs (9-17kg)

2x 25/551 Tablets => 50 mg AS and 100mg

base of mefloquine

2.9 5.5 6.4 12.2

5.8 11.1

7-12 yrs (18-29kg)

1x 100/2202 mg Tablet => 100 mg AS and 200mg

base of mefloquine

3.4 5.5 7.5 12.2 6.8 11.1

>13 yrs (>30kg)

2x 100/2202 mg Tablets =>200 mg AS and 400mg

base of mefloquine

2.8 6.6 6.2 14.6 6.6 13.3

1 Mefloquine HCl 55 mg is equivalent to 50 mg of mefloquine 2 Mefloquine HCl 220 mg is equivalent to 200 mg of mefloquine

9.2 Reference to existing WHO and other clinical guidelines

� Both, artesunate (AS) and mefloquine (MQ) are included in the WHO Model List of Essential Medicines for Children and at the 17th edition of the WHO Essential

Medicines Model List.3

� The 17th edition (March 2011) EML list currently recommends that medicines for the treatment of P. falciparum malaria cases should be used in combination, recognizing that not all antimalarial recommended by WHO exist as FDCs and encourages their development and rigorous testing.

� Since 20014 the combination of AS+MQ has been one of the WHO-recommended ACTs for first-line antimalarial treatment.5

� ASMQ FDC is pre-qualified by WHO since September 2012.32


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� ASMQ is the national malaria policy in selected countries in WHO regions.10 -33

9.3 Need for special diagnostic or treatment facilities and skills

The WHO Global Malaria Programme issued revised guidelines for the treatment of malaria5 in which it was recommended that all suspected cases of malaria receive a diagnostic test prior to treatment. Prompt parasitological confirmation by microscopy, or alternatively by RDTs is recommended in all patients with suspected malaria before treatment is started. Antimalarial treatment solely on the basis of clinical suspicion should only be considered when a parasitological diagnosis is not accessible. One of the greatest limitations to ensuring access to early diagnosis and effective treatment is the lack of adequately trained, motivated human resources in public health, including program managers, doctors, nurses, pharmacists, laboratory technicians, data managers and other skilled health providers. The challenge for a clinician working in a malaria-endemic area is managing a febrile patient who does not have malaria. Clinicians are more likely to adhere to the results of a malaria test when they can perform a comprehensive assessment of the patient to identify and treat other diseases. For this to be effective, additional diagnostic tools must be available to health workers, which are appropriate to the setting, including clinical diagnostic equipment and additional laboratory tests such as urine dipsticks. The appropriate medicines for treating common causes of fever (e.g. antibiotics for pneumonia, oral rehydration salts and zinc for diarrhea) should also be available.34 10. Summary of comparative efficacy in a variety of clinical settings:

10.1 Identification of clinical evidence

Published studies concerning the use of artesunate and mefloquine, were identified through electronic searches and by manually searching the reference lists of studies, regardless of language of publication or study site (comparative and non-comparative clinical trials), using any formulation of AS administered over 3 days and MQ concomitantly or sequentially, for treating uncomplicated falciparum malaria with follow-up of at least 28 days.

10.2 Summary of available data

The extensive use of artesunate plus mefloquine in which these drugs have been administrated as different regimens from various commercial brands, in both adults and children, in non-fixed combination or as co-blister formulations, supports the clinical efficacy of these drugs. As such, a full development program of clinical studies to support the use of the ASMQ FDC tablets was not considered necessary for these two well-established antimalarial drugs.

10.2.1 Available data of artesunate plus mefloquine as Loose Combination: Clinical data is reported from ~ 14000 patients treated with various regimens of AS+MQ in 90 open and randomized trials conducted in 20 countries from 3 continents since 1992. See full details in Appendixes 1 and 2 at the end of this dossier.

Clinical evidence on the use of oral AS and MQ in non-fixed combination or as co-blister formulations is mainly available from Southeast Asia (N=9337), in particular from Thailand where 31 clinical studies reported data from 7352 patients treated with AS+MQ since 1992. Additional results on the use of AS+MQ in non-fixed combination or as co-blister formulations are published for other Asian countries from 3835 patients receiving AS+MQ for uncomplicated malaria since 1997. (Cambodia N=1419; Myanmar N=1298; Laos N=368; Vietnam N=507; India N=122 and Bangladesh N=121). The use of AS+MQ in non-fixed combination or as co-blister formulations has also been documented in Africa; eleven countries provided data of patients (N=1968) treated with various dose regimens of AS+MQ as loose combination from 1994.


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Another continent where AS+MQ in non-fixed combination or as co-blister formulations has been used is Latin-America. Nine small studies conducted in Peru, Colombia, Bolivia and Ecuador, reported data from 921 patients since 2000.

10.2.2 Available data of artesunate plus mefloquine as Fixed-Dose Combination: The ASMQ FDC Development Program provided additional data on the clinical performance of ASMQ FDC tablets 25 / 55 mg and 100 / 220 mg; See section 10.4 below

10.3 Summary of available estimates of comparative efficacy: Almost 4.500 patients treated with AS+MQ (AS 3 days and MQ 25 mg/kg) for uncomplicated malaria have been assessed in comparative studies with either: AL, DHA-PQ or AS-Pyr. The randomized studies were performed in Asia (Thailand, Cambodia, Myanmar, Laos, Vietnam, Bangladesh & India) in Latin America (Colombia and Peru) and in Africa (Senegal, Mali, Cote d’Ivoire, Burkina Faso and Tanzania). The PCR corrected cure rates with AS+MQ ranges from 92, 4% in Cambodia in 2004 to 100% in several studies. See Table I for full details.

Table I. Comparative studies using artesunate plus mefloquine over 3 days, all PCR corrected

Year/ Country/ Location

Author Year of Study

Drugs: AS 3 days + MQ 24-25 mg/Kg Number and age of patients treated with AS+MQ

AS+MQ Cure rate PCR corrected

Comparative studies using artesunate plus mefloquine and artemether-lumefantrine

199835 Thailand Mae La

van Vugt M 1995-1996 AS (Guilin) +MQ (Hoffman-La Roche) and artemether-benflumetol

N=308 5-66 yr

94%

200036 Thailand Bangkok and Mae La

van Vugt M 1997- 1998 AS (Guilin) +MQ (Hoffman-La Roche) and AL N=50 3-61 yr

100%

200137 Thailand Bangkok

Lefevre G 1998-1999 AS (Guilin) +MQ (Hoffman-La Roche) and AL

N=55 >12 yr

100%

200538 Thailand Mae La and Mawker Tai

Hutagalung R 2001- 2002 AS (Guilin) +MQ (Hoffman-La Roche) and AL N=245 2-72 yr

96,3%

200639 Cambodia-Battambang

Denis MB 2003-2004 AS (Mediplantex)+MQ (PharmaDanica) and AL N=52 15 -50 yr

92,4%

201040 Myanmar Rakhine, Kachin and Shan States

Smithuis F 2008-2009 ASMQ (Farmanguinhos) and AS+MQ (Manufacturer non specified) and AL and DHA-PQ and ASAQ

N=169 & 161 >1yr and adults

100% and 98,7%

200441 Laos Savannakhet

Mayxay M 2002 to 2003 AS (Guilin) +MQ (Roche), CQ+SP and AL N=110 >1yr and adults

100%

200442 Laos Luang Nahtha

Stohrer JM 2003 AS (Mepha) +MQ (Mepha) and AL N=53 2-66 yr

100%

200543 Bangladesh, Chittagong Hills

van den Broek IV 2003 AS +MQ (Manufacturer non specified), CQ+SP and AL

N= 121 1.2 m -80 yr

100%


15

200744 Senegal Richard Toll & Podor (North); Guediawaye & Kaolack (Central) and Velingara (South)

Faye B 2003- 2004 AS (Mepha) + MQ (Mepha) , AS+AQ, AL and AQ+SP

N=145 >2-65yr

100%

200845 Mali Kambila

Sagara I 2004-2005 AS+MQ (Mepha and AL N=232 >1-70yr

96,04%

201026Senegal Ndoffane and Kaolack

Faye B 2008 AS+MQ (Artequin™ Pediatric Mepha) and AL N=154 2-7 yr

100%

201146 Côte d’Ivoire Anonkoua Kouté

Toure OA 2007 AS+MQ (co-formulated Mepha) and AL N=75 6-59 months

99%

201247 Colombia Tumaco

Carrasquilla G 2007-2008 AS+MQ (Mepha) and AL N=53 12-65 yr

100%

9 studies From 1995 to 2009

1983 patients 92,4 to 100%

Comparative studies using artesunate plus mefloquine and ddihydroartemisinin-piperaquine

200448 Thailand Mae La, Mawker Thai and Munruchai

Ashley EA 2002-2003 AS (Guilin) +MQ (Atlantic), DHA-PQ and DHA-PQ+AS

N=176 1-65 yr

94,9%


Ashley EA 2003-2004 AS (Guilin) +MQ (Atlantic) and DHA-PQ N=166 1-55 yr

95,7%

201049 Thailand Bangkok, Ratchaburi and Tak

Valecha N 2005-2007 AS (Mepha) +MQ (Mepha) and DHA-PQ (Sigma Tau)

N= 234 3m – 65 yr

97%

200750 Cambodia-Oddar Meanchey and Siem Reap

Janssens B 2002-2003 AS (Guilin) +MQ (Mepha) and DHA-PQ N=195 1-57 yr

97,5%

200651 Myanmar Rakhine State

Smithuis F 2003-2004 AS (Guilin) +MQ (Hoffman-La Roche) and DHA-PQ (both supervised and unsupervised)


99,4 % and 100%


Smithuis F 2008-2009 ASMQ (Farmanguinhos) and AS+MQ (Manufacturer non specified) and AL and DHA-PQ and ASAQ


100% and 98,7%


Mayxay M 2004 AS (Guilin) +MQ (Roche) and DHA-PQ N=107 >1 yr and adults

99%


Mayxay M 2005- 2006 AS (Mepha) +MQ (Mepha) and DHA-PQ N=98 3m – 65 yr

100%

200454 Vietnam Ho Chi Minh and Binh Phuoc

Hien TT 2001 AS (Guilin) +MQ (Hoffmann-La Roche), DHA-TP and DHA-PQ

N=38 & 77 8-56 yr

100% and 98,7%

201049 India Assam, Goa and Mangalore

Valecha N 2005-2007 AS (Mepha) +MQ (Mepha) and DHA-PQ N= 49 3m – 65 yr

97%

200755 Peru Iquitos

Grande T 2003-2005 AS (Guilin) +MQ (Hoffman La-Roche) and DHA-PQ

N=260 5-60 yr

99,6%


16


2055 patients 94,9 to 100%

Comparative studies using artesunate plus mefloquine and artesunate-pyronaridine

201256 Thailand Mae Sot and Mae Ramat

Rueangweerayut R 2007-2008 AS (Mepha) +MQ (Mepha) and AS-Pyr N= 88 & 94 3-60 yr

96,6% and 94,7%

201256 Cambodia-Pailin

Rueangweerayut R 2007-2008 AS (Mepha) +MQ (Mepha) and AS-Pyr N= 42 3-60 yr

100%

201256 Vietnam Ho Chi Minh and Hanoi

Rueangweerayut R 2007-2008 AS (Mepha) +MQ (Mepha) and AS-Pyr N=42 & 13 3-60 yr

100% and 100%

201256India Mangalore


100%

201256 Burkina Faso, Tanzania & Côte d’Ivoire


100%


368 patients 94,7 to 100%

10.4 Available data of artesunate plus mefloquine Fixed-Dose Combination: Critical elements in the ASMQ FDC development program 10.4.1 Pharmacokinetics and comparative bioavailability of artesunate and mefloquine administered separately or as a fixed combination product

to healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria.57 A single-dose, randomised, crossover design study in healthy volunteers and a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria to assess the pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine. The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in healthy volunteers and uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% bioequivalence limits. For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated and separate products extended below the 80% limit; AUC and Cmax values were 15-25% and 25-40% lower than those observed after administration of the separate products. These differences in the exposure to artesunate/dihydroartemisinin are unlikely to be considered of clinical relevance as plasma concentrations exceeded the minimum parasiticidal concentrations of P. falciparum.

10.4.2 Population Pharmacokinetic Assessment of a New Regimen of mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria.24A multiple-dose, randomised, controlled, parallel-group, open-label and phase II study in adults with mono infection with P. falciparum malaria: this study was designed to develop a population pharmacokinetic model describing the M888 dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modelling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each


17

resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

10.4.3 New fixed dose artesunate/mefloquine for treating multidrug resistant Plasmodium falciparum in adults, a comparative phase IIb safety,

monitoring of cardiovascular effects and pharmacokinetic study with standard dose non-fixed artesunate plus mefloquine.58-59 The new fixed dose artesunate (AS)/mefloquine (MQ) was assessed in adults, hospitalized for 28 days, with uncomplicated, drug resistant falciparum malaria. Patients (n=25/arm) were treated with: (i) two fixed dose tablets (AS/MQ arm: AS 100 mg/MQ 200 mg/tablet) daily for 3 days or (ii) non fixed AS (AS+MQ arm: 4 mg/kg/d x 3d) + MQ (15 mg/kg D1, and 10 mg/kg D2), dosed by weight. Clinical, laboratory, ECG adverse events (AEs), efficacy, pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs, malaria induced hypotension occurring in the AS/MQ arm, necessitated rescue treatment. There were no significant changes in haematology, biochemistry, PR and QRS intervals. For all patients, mean Fridericia corrected QT intervals were significantly prolonged on D3 (407 ms) and D7 (399 ms) vs. D0 (389 ms) in parallel with significant falls in heart rates [67 (D3), 73 (D7), 83 (D0) beats /minute]. Fixed-non fixed formulations were bioequivalent for MQ but not for AS and DHA. One AS/MQ patient developed a new infection on D28; his D28 plasma MQ concentration was 503.8 ng/mL. Fixed dose AS/MQ was well tolerated and had broadly similar PK profiles to non-fixed AS+MQ and is considered a suitable replacement.

10.4.4 A randomised comparative study of a new fixed combination of mefloquine artesunate compared to the separate drugs for the treatment

of uncomplicated multidrug resistant falciparum malaria.60 A multiple-dose, randomised, controlled, parallel-group, open-label and pivotal phase III study in adults and children with mono infection with P. falciparum or mixed infection with P. vivax. The new fixed combination of mefloquine plus artesunate was compared with the conventional regimen of separate tablets for the treatment of uncomplicated multidrug-resistant falciparum malaria. On the north-western border of Thailand 500 adults and children with uncomplicated falciparum malaria were randomized to receive either the new fixed combination or separate tablets. The day 63 polymerase chain reaction-adjusted cure rates were 91.9% (95% CI 88.2–95.6) in the fixed combination group and 89.2% (85.0–93.4) in the loose tablets group (P ¼ 0.3). There was a lower incidence of early vomiting in the group receiving the fixed combination. This new fixed combination of mefloquine and artesunate was efficacious, well tolerated and convenient to administer.

10.4.5 A Phase III, open-label, single-arm study conducted in two sites in India (Goa and Mangalore) assessed pharmacokinetics, safety and

efficacy of ASMQ FDC tablets61in adult patients aged 18 to 55 years with uncomplicated P. falciparum malaria. The D63 Polymerase Chain Reaction-adjusted cure rates from the 66 subjects that completed the D63 follow-up was 100%. 98.6% of patients had parasite counts of 0 at 48 hours after the first dose. The median parasite clearance time in patients was 48 hours, while the median fever clearance time was 8 hours. During the entire study, there were no early treatment failures, late clinical failures, mixed infections or severe malarial infections. In patients who tested positive for gametocytes at Day 0, the median time to a gametocyte count of 0 was 7 days, while all patients who tested positive for gametocytes after Day 0 were cleared by Day 3.

10.4.6 An open label, intervention and implementation study in Brazil62 to evaluate the impact of programmatic use of ASMQ FDC in the reduction of P.

falciparum malaria incidence in comparison with the standard antimalarial regimen used in Brazil. This effectiveness study has been conducted in seven municipalities in the Acre region in the Amazonia. Patients were administered one or two tablets of ASMQ FDC (25/55 mg or 100/220 mg) daily for 3 days, or the standard regimen of quinine plus doxycycline and primaquine. Patients were followed-up on D7 and D40, and a thick blood smear analysis performed. The total population who received ASMQ between June 2006 and December 2008 numbered 23,845. A significant effect of the ASMQ intervention was observed in all evaluated outcomes [Incidence Rate 0.34 (0.20–0.58); Ratio Falciparum/Vivax 0.67 (0.50–0.89); Admissions 0.53 (0.41–0.69)], with a decrease in the mean level of the time series, adjusted for the trend and seasonality. Interaction effects between months and intervention were also evaluated. An elimination of the end of the year seasonal malaria peak was seen post-intervention. No serious adverse events relating to the use of fixed-dose ASMQ were reported. Authors concluded that in the remote region of the Jurua´ valley, the early detection of malaria by health care workers and treatment with fixed-dose ASMQ was feasible and efficacious, and significantly reduced the incidence and morbidity of multidrug-resistant Pf.


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10.4.7 Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria.40 An open randomized comparison of the effectiveness of four fixed-dose ACTs and loose artesunate–mefloquine in Burmese adults and children. The effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate–mefloquine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, artemether– lumefantrine) and loose artesunate–mefloquine were compared in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 2008 and March 2009 in Burmese adults and children older than 6 months with acute uncomplicated Plasmodium falciparum malaria or mixed infection. All patients were also randomly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not. Patients were followed up for 63 days. 155 patients received artesunate–amodiaquine, 162 artemether–lumefantrine, 169 artesunate–mefloquine, 161 loose artesunate–mefloquine, and 161 dihydroartemisinin–piperaquine. By day 63 of follow-up, 14 patients on artesunate–amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether–lumefantrine (two patients), fixed-dose artesunate–mefloquine (0 patients), loose artesunate–mefloquine (two patients) and dihydroartemisinin–piperaquine (two patients). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0·75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11·9. All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment. As conclusion, artesunate–mefloquine provided the greatest post-treatment suppression of malaria. Adding a single dose of primaquine would substantially reduce transmission potential. Vivax malaria, not recurrent falciparum malaria, is the main complication after treatment of P falciparum infections in this region.

10.4.8 Ongoing ASMQ FDC Clinical Studies

� A multicentre, open-label, prospective, randomised, controlled, Phase IV study in Africa,63 will assess efficacy, safety and pharmacokinetics of ASMQ FDC in 940 children with uncomplicated P. falciparum malaria from Tanzania, Burkina Faso and Kenya versus artemether-lumefantrine. [DNDi study] � A open-label, randomised, phase III trial 64will assess efficacy, safety and pharmacokinetics of ASMQ FDC and dihydroartemisinin–piperaquine in about 3,500 pregnant women (2nd and 3rd trimester) with uncomplicated malaria from Burkina Faso, Ghana, Malawi and Zambia compared with ASAQ FDC and artemether– lumefantrine. [PI led study-EDCTP & Umberto D’Alessandro]

� An open-label phase II and III trial65 to estimate the pharmacokinetic profile of ASMQ FDC for treatment of P. falciparum or mixed infection in 48 pregnant women (2nd and 3rd trimester) in Burkina Faso compared to non-pregnant women. [PI led study]

� An open label, randomized, interventional study phase I and II66 to compare the safety, tolerability and efficacy of bi-monthly intermittent preventive treatment with either artesunate plus mefloquine or amodiaquine plus sulfadoxine-pyrimethamine with the standard regimen of daily proguanil for the prevention of malaria and related complications in patients with sickle cell anemia in Nigeria. [PI led study] � A multi-center, open-label, randomized trial of chloroquine, artemether-lumefantrine, and mefloquine-artesunate for the treatment of uncomplicated P. vivax malaria in pregnant women in Brazil67 to assess safety and efficacy of 3 different regimens: chloroquine, artemether-lumefantrine and mefloquine-artesunate for the treatment of uncomplicated P. vivax malaria parasitemia in pregnant women in Brazil. The data from this study will be used to determine future national malaria treatment policies.


19

� A single, prospective, non-randomised, effectiveness trial 68 of ASMQ FDC in Juruá Valley, State of Acre, Brazil will evaluate clinical and parasitological responses of 100 individuals with uncomplicated malaria by P. falciparum treated with ASMQ FDC for three days and monitored clinically and biochemically for 42 days. [PI led study] � A randomised, open-label, phase III trial 69will assess efficacy, safety and pharmacokinetics of ASMQ FDC and dihydroartemisinin– piperaquine in about 1,000 pregnant women (2nd and 3rd trimester) with uncomplicated malaria from Thailand compared with artemether–lumefantrine. [PI led study-Prof. François Nosten]

� A Phase III prospective, randomized, controlled, open and non- comparative in 264 patients in Brazil (Rondonia) will evaluate the safety and efficacy of artemisinin-based combination therapy for the treatment of uncomplicated P. vivax Malaria, comparing ASMQ to AL and chloroquine, all followed by primaquine. [PI led study]

11. Summary of comparative evidence on safety: The rational of ASMQ FDC development

As explained above, the rational for the development of the Fixed-Dose Combination tablets of artesunate plus mefloquine was the need to improve the effectiveness of artesunate plus mefloquine [already in use as loose combination for the treatment of uncomplicated malaria since 1992], as per the 2001 WHO recommendations concerning ACT and further ratified as a public health imperative. Published data for the safety of AS and MQ administered separately and together in the standard regimen are reviewed below. Safety and tolerability profiles of both AS and MQ are well established70, and drug-related toxicity profiles of both drugs are referred to in standard texts (Dollery-artemisinin71; Dollery-mefloquine72; Meyler’s Side Effects of Drugs73; Martindale, The Complete Drug Reference74; Physicians’ Desk Reference75; Roche Products Limited. Lariam® Summary Product Characteristics.76)

11.1 Estimate of total patient exposure to date

AS and MQ are well-established drugs for the treatment of P. falciparum malaria. Separately and combined, a considerable number of patients have been exposed to the drugs. Data from clinical settings is reported from more than 14.000 patients treated with AS+MQ (loose combination or co-blisters) in 90 open and randomized trials conducted in 20 countries from 3 continents since 1992. See Appendixes 1 and 2. It should be noted that figures presented here are the documented bulk of patients treated with AS+MQ, however much larger number of patients have been exposed worldwide to AS+MQ loose combination or co-blisters. Additional 24.000 patients with uncomplicated malaria were treated with ASMQ fixe-dose combination, so a total of more than 38.000 patients with uncomplicated malaria have been documented following treatment with commercial brands of either loose or fixed dose combination of AS+MQ. Since its launch in Brazil in 2008 until June 2012, ~260.000 treatments of ASMQ FDC have been produced by Farmanguinhos, and subsequently made available at no cost for field distribution by the Brazilian government. More than 30.000 treatments were donated to NMCPs for implementation studies (including 4. 000 treatments in Bolivia and 26.000 in Cambodia) in order to accelerate ASMQ use and data collection for further ASMQ FDC deployment.77 In 2012, Cipla had deployed ASMQ FDC in the private sector in India, where more than 20.000 treatments have been provided for the treatment of uncomplicated malaria in adult patients.


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The general lack of standardization in recording and reporting of adverse events unfortunately precludes the use of meta-analysis of safety data.12 However, a single centre in the Thai-Myanmar border pooled data from 16 clinical trials conducted between January 1992 and June 2005. An individual Patient Meta-Analysis of mefloquine-artesunate tolerability from 5.487 patients treated for P. falciparum malaria along the Thai-Myanmar border was performed78 and is currently being enlarged with approximately 7.000 patients and revised by Prof. Nosten for publication. A total of 5.487 patients randomly assigned to receive one of 10 different dosing and timing schedules of artesunate 4 mg/kg/d once daily for 3 days combined with mefloquine 15 mg/kg (M15) or mefloquine 25 mg/kg (M25) over 1 to 3 days. In the M25 groups, patients who were younger, febrile or vomiting on admission before treatment were at higher risk for drug vomiting while the risk of early vomiting was decreased when treating with M888/FDC or administering artesunate before mefloquine. Splitting the dose of mefloquine significantly reduced the incidence of gastrointestinal AEs (abdominal pain, anorexia, nausea, and late vomiting), as well as experiencing any AE. The M888/FDC groups were at lower risks for anorexia, muscle pain, palpitation, and fatigue compared to the M25 SD groups. The incidence of serious neurological reaction of all MAS combinations was 2 per 1000 but dose effect might induce an increase in neuro-psychiatric risks. As conclusion: MAS3 is comparatively well tolerated for treatment of primary infections. M888/FDC offered the best safety profile.

11.2 Description of adverse effects/reactions

• Artemisinin and its derivatives are safe and remarkably well tolerated. There have been reports of mild gastrointestinal disturbances, dizziness, tinnitus, reticulocytopenia, neutropenia, elevated liver enzyme values, and electrocardiographic abnormalities, including bradycardia and prolongation of the QT interval, although most studies have not found any electrocardiographic abnormalities. The only potentially serious adverse effect been reported with this class of drugs is type 1 hypersensitivity reactions in approximately 1 in 3000 patients. Neurotoxicity has been reported in animal studies, particularly with very high doses of intramuscular artemotil and artemether, but has not been substantiated in humans. Similarly, evidence of death of embryos and morphological abnormalities in early pregnancy has been demonstrated in animal studies. Artemisinin has not been evaluated in the first trimester of pregnancy so should be avoided in first trimester patients with uncomplicated malaria until more information is available.5 • Minor adverse effects are common following mefloquine treatment, most frequently nausea, vomiting, abdominal pain, anorexia, diarrhea, headache, dizziness, loss of balance, dysphoria, somnolence and sleep disorders, notably insomnia and abnormal dreams. Neuropsychiatric disturbances (seizures, encephalopathy and psychosis) occur in approximately 1 in 10 000 travelers receiving mefloquine prophylaxis, 1 in 1000 patients treated in Asia, 1 in 200 patients treated in Africa, and 1 in 20 patients following severe malaria. Other side effects reported rarely include skin rashes, pruritus and urticaria, hair loss, muscle weakness, liver function disturbances and very rarely thrombocytopenia and leucopenia. Cardiovascular effects have included postural hypotension, bradycardia and, rarely, hypertension, tachycardia or palpitations and minor changes in the electrocardiogram. Fatalities have not been reported following overdosage, although cardiac, hepatic and neurological symptoms may be seen. Mefloquine should not be given with halofantrine because it exacerbates QT prolongation. There is no evidence of an adverse interaction with quinine. 5

• Artesunate and mefloquine in combination for AS+MQ loose tablets

a) Price et al reported prospective studies of acute uncomplicated, multidrug-resistant P. falciparum malaria on the western border of Thailand79 in which oral artemisinin derivatives and MQ (15 to 25 mg/kg) were administered together as well as separately. A total of 2.862 patients received both drugs. Detailed neurological examinations were conducted in children older than 5 years. The combined regimens of MQ plus an artemisinin derivative were associated with significantly more side effects than those with an artemisinin derivative alone, as shown in the table below:


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Reported Adverse Events following administration of mefloquine alone, artemisinin derivative alone or both in combination

Adverse Event MQ Alone MQ Plus Artemisinin Derivative Artemisinin Derivative Alone

Acute Nausea 46% 31%1 16%

Vomiting 24% 24%1 11%

Anorexia 54% 51%1 34%

Dizziness 54% 47%1 15%

Diarrhoea 3% 3% 1% 1 p<0.001 vs. Artemisinin Derivative Alone Data source Price et al 1999

On Day 2 of treatment, six patients (One patient treated with MQ plus artemisinin derivative and five patients treated with artemisinin derivative alone) developed neurological signs including heel toe ataxia, positive Romberg's sign, nystagmus and impaired finger dexterity. These signs were significantly associated with dizziness. On Day 7, four further patients developed neurological signs including heel toe ataxia, a positive Romberg's sign, nystagmus and dizziness, headache and weakness. All neurological signs resolved. There was no association between neurological symptoms/signs and type or dose of artemisinin derivative. No patient developed deafness, or permanent neurological abnormalities. These data suggest that short course therapy with the artemisinins, either alone or in combination with MQ, was associated with self limiting, minor neurological deficits in a minority of patients during the first few days of P. falciparum malaria. b) A study on the Thailand-Myanmar border found no evidence of auditory toxicity with AS plus MQ administered in combination.80 c) The “Adverse event reporting” from the mefloquine-artesunate meta-analysis of 5.487 patients treated for P. falciparum malaria along the Thai-Myanmar border, 78 overall shows comparable adverse events to those previously reported in the clinical literature. The most frequently occurring adverse events for both regimens are presented in the following table. A similar adverse event profile was observed for treatment regimens M25 SD and M888/FDC.

Mefloquine-artesunate meta-analysis; most frequent adverse events The two regimens most closely associated with the clinical studies concerning ASMQ FDC were M25 SD split dose

regimen (MQ given over 2 days) and the M888/FDC regimen (MQ given over 3 days) Adverse Event Treatment Group

M25 SD (MQ Given over 2 days) M888/FDC (MQ Given over 3 days)

% %

Abdominal pain 10.8 13.2

Anorexia 35.7 44.2

Dizziness 33.0 38.3


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Mefloquine-artesunate meta-analysis; most frequent adverse events The two regimens most closely associated with the clinical studies concerning ASMQ FDC were M25 SD split dose

regimen (MQ given over 2 days) and the M888/FDC regimen (MQ given over 3 days) Adverse Event Treatment Group

M25 SD (MQ Given over 2 days) M888/FDC (MQ Given over 3 days)

% %

Fatigue 7.4 13.6

Headache 28.0 33.3

Joint pain 10.6 13.4

Nausea 20.9 18.2

Palpitation 13.1 16.6

Sleep disturbance 21.6 25.9

Vomiting 14.3 12.9

% Percentage of patients Data source Mefloquine-artesunate meta-analysis (Zwang et al 2010; unpublished data)

The overall incidence of early vomiting (i.e. within 1 hour of drug administration) was 3.3% (95% CI: 2.8 - 3.8%). The administration of MQ as a single dose resulted in higher incidence of early vomiting. Splitting the dose of MQ reduced the incidence of early vomiting slightly compared with the average for all studies: regimen M25 SD 3.0% (95% CI: 2.3 - 3.8%), regimen M888/FDC 3.0% (95% CI: 1.7 - 4.4%). Giving MQ as a split dose or after the first AS dose reduced the risk of early vomiting compared to the MQ 25 mg/kg on Day 0 regimen (IRRMH 0.49, 95% CI: 0.29 - 0.82, p=0.007, stratified by age). This was also true in younger patients (aged 0 to 4 years; AOR 0.51, 95% CI: 0.30 - 0.86%, p=0.012). Overall, the meta-analysis indicated that by splitting the dose of MQ into two or three doses, a protective effect on early vomiting (an important determinant of cure) was observed. Compared with regimens using MQ as single doses, the combinations using split doses of MQ reduced the risk of:

• Early vomiting (See above), • Nausea (IRRMH 0.60, 95% CI 0.51 - 0.71, p=0.001), • Abdominal pain (IRRMH 0.66, 95% CI 0.54 - 0.79, p=0.001), • Anorexia (IRRMH 0.80, 95% CI 0.68 - 0.94, p=0.008), • Vomiting (IRRMH 0.72, 95% CI 0.60 - 0.87, p=0.001).

Patients treated with M25 SD or M888/FDC were at lower risk of reporting one of the 10 most common adverse events (IRR 0.90, 95% CI 0.81 - 0.99, p=0.034). The incidence risk ratios (Stratified for age) were lower in the M888/FDC group compared to the M25 SD group for:


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• Anorexia (IRR 0.79, 95% CI 0.60 - 1.04, p=0.093), • Palpitation (IRR 0.75, 95% CI 0.54 - 1.05, p=0.095), • Fatigue (IRR 0.52, 95% CI 0.39 - 0.69, p=0.001), • Muscle pain (IRR 0.50, 95% CI 0.30 - 0.82, p=0.009).

A higher risk for hearing disturbance was observed in the M888/FDC group (IRR 3.33, 95% CI 1.69 - 6.53, p=0.001, stratified by age), however the prevalence rate for both regimens was lower than 0.2% at Day 28 and the first week captured more than 90% of the entire incidence. Serious or Significant Adverse Events:

Three reported deaths (0.5 per 1000, 95% CI 0.2-1.8) were not related to the drug regimen; one death was related to a family fight. One 17 year-old male patient died; the patient had a 3-months history of swollen ankles and peripheral paraesthesia, considered probably due to adult beri beri. One 35 year-old female recovered rapidly from malaria with no adverse sequelae, she returned to Myanmar and died 2 weeks later, but no further details were available. Overall in the meta-analysis, 12 patients were reported with either seizure or neuro-psychiatric adverse event. A total of five patients had generalized tonic clonic seizures, and two of these patients were young children. At least two of these patients had a known history of epilepsy. In the proposed Summary of Product Characteristics for ASMQ FDC tablets, it is proposed that epilepsy is a contraindication to using MQ, and is defined as a contraindication for ASMQ FDC tablets. The crude incidence rate was 2 per 1000 (95% CI: 1.3–4.0 per 1000). Serious adverse events are presented by treatment regimen in the following table: Mefloquine-artesunate meta-analysis; Serious Adverse Events

Regimen Serious Adverse Event

M15 D0 Two patients had serious neuro-psychiatric adverse events: one woman had a depressive syndrome and one 12-year-old girl developed an acute psychotic episode.

M25 D0 One 57-year-old patient, had an episode of hypertonia, generalized shaking, and brief unresponsiveness associated with a high fever on Day 1. This adverse event could possibly be categorized as rigors.

M25 D1 One adult female patient with known epilepsy suffered repeated tonic clonic fits 24 hours after her dose of MQ One adult female patient suffered from anxiety, palpitations and sleeping disturbances one week after receiving MQ.

M25 D2 A 6-year-old boy with a history of epilepsy was reported with seizure two weeks later Seizures were also reported for a 31-year-old woman A total of five patients (two adults, three children) developed frank haemoglobinuria within 24 of AS administration.

M25 SD Seizures were reported for a 22-year-old man One case of transient urticaria reported Two patients required rescue treatment, of which one (a child) required hospitalization for intravenous fluids.

M888 One case of urticaria reported.

FDC Two cases of transient urticaria reported.

Data source Mefloquine-artesunate meta-analysis (Zwang et al 2010; unpublished data)


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• Artesunate and mefloquine in fixed-dose combination : Summary and description of completed Clinical Safety Studies with ASMQ FDC

Summary Description of Completed Clinical Safety Studies

Study Number and Objective Total Number of Subjects Dose and Regimen

Duration of Study

Number Patients Receiving ASMQ FDC Tablets

Key Safety Data

ASMQ-HNV study (Pharmacokinetics Study in Healthy Normal Volunteers)57 A single-dose two-phase crossover study to assess the tolerability and PK parameters of a fixed-dose formulation of artesunate-mefloquine and standard dose artesunate and mefloquine as loose tablets in healthy normal volunteers. Report dated 11th October 2007 Publication: Olliaro et al. 2010

24 healthy volunteer subjects, 12 subjects per treatment arm. ASMQ FDC Tablets: 2 x tablets AS 100 mg + MQ 200 mg; Total ASMQ FDC dose of AS 200 mg plus MQ 400 mg. Comparator loose tablets AS and MQ: 4 x AS 50 mg tablets (Arsumax®, Sanofi-Aventis, France), giving a total dose AS 200 mg; 2 x MQ 250 mg tablets (Lariam®, Roche, Basel, Switzerland), giving a total dose MQ 500 mg. Single dose of test or reference IMP on Day 0 with 90 day washout period between the two phases of the crossover study

1 day of dosing. Duration of up to 180 days

24 No SAEs and no TEAEs that led to withdrawal from the study. TEAEs were reported by 5 subjects (20.8%) in ASMQ FDC group and 10 subjects (41.7%) in loose tablets group. All TEAEs were mild and not considered related to IMP. 7 (53.8%) subjects reported blood and lymphatic system disorders, with 4 TEAEs (eosinophilia) in ASMQ FDC group and 4 TEAEs (3 of eosinophilia, 1 of thrombocytopenia) in loose tablets group. 5 (38.5%) subjects reported renal and urinary disorders; all were in the loose tablets group. 2 subjects (15.4%) reported gastrointestinal disorders, with 1 TEAE (diarrhoea) in ASMQ FDC group and 2 TEAEs (diarrhoea) in loose tablets group. Median changes over time in laboratory parameters were similar between treatments. No reports of clinically significant laboratory abnormalities during the study. No clinically significant vital signs, ECG or physical examination findings for any subject.

ASMQ-BKK study (Phase II Study in patients)58 A randomised, open label study to assess the efficacy, safety and PK parameters of a fixed dose formulation of artesunate mefloquine and standard dose artesunate and mefloquine as loose tablets for the treatment of acute, uncomplicated

50 adult patients with slide proven P. falciparum malaria randomised to one of the two treatments: ASMQ FDC Tablets: ASMQ FDC Tablets (2 x tablets): AS 100 mg + MQ 200 mg, given once daily for 3 days (Days 0, 1 and 2). Fixed daily dose of AS 200 mg + MQ 400 mg; total dose AS 600 mg + MQ 1200 mg.

28 days 25 TEAEs were reported in 24 (96.0%) patients in ASMQ FDC group and 25 (100.0%) patients in loose tablets group. All but 2 AEs were mild. One TEAE (recrudescence of malaria observed on Day 28) was considered related to study medication. No deaths reported. 2 SAEs of severe hypotension led to patients'


25



Duration of Study


Key Safety Data

P. falciparum malaria. Report dated 19th December 2008 Publication: Krudsood et al. 2010

Comparator loose tablets AS and MQ: AS 50 mg tablets (Arsumax®, Sanofi-Aventis, France) and MQ 250 mg tablets (Lariam®, Roche, Basel, Switzerland): Dosing utilised the standard split-dose regimen for co-administration of these agents: AS total dose of 12 mg/kg, given as 4 mg/kg/day for 3 days; resulting daily total dose of 162.5 to 237.5 mg/day based on body weight measured on the first day of treatment. MQ total dose of 25 mg/kg given as divided dose 15 mg/kg/day and 10 mg/kg/day on the second and third day of treatment, respectively; resulting daily dose of 625 to 1000 mg and 375 to 625 mg on the second and third day of treatment, respectively, based on body weight

discontinuation; hypotension was not considered related to study IMP, but was probably malaria-related. Most frequently reported TEAEs were: blood and lymphatic system disorders (eosinophilia and anaemia) in 20 (83.3%) patients in ASMQ FDC group and 21 (84.0%) patients in loose tablets group; infections / infestations in 17 (70.8%) patients in ASMQ FDC group and 8 (32.0%) patients in loose tablets group; gastrointestinal disorders in 6 (25.0%) patients in ASMQ FDC group and 8 (32.0%) patients in loose tablets group. Median changes over time in laboratory parameters were similar between treatments. Thrombocytopenia, leukopenia, neutropenia and elevated platelet levels (Day 7) were observed, but were not considered related to study IMP. No clinically significant vital signs, ECG or physical examination findings for any subject.

Pivotal Study: ASMQ-Mae Sot study (Phase III Study in patients) 60 A Randomized, Open Study to Assess the Safety and efficacy of a new artesunate-mefloquine co-formulation With an Equivalent Dose Regimen of the Individual Drugs for the Treatment of Acute Uncomplicated P. falciparum malaria Report dated 12th September 2006 (V02) Publication: Ashley et al 2006

500 adults and children with slide proven mono- or mixed infection of P. falciparum malaria, randomised to one of the two treatments: ASMQ FDC Tablets: ASMQ FDC Tablets dosed using the four age and weight-based dosing categories, presented in the Summary of Product Characteristics (See also Table 2.7.4-5): 1x or 2x ASMQ FDC tablet(s) 25/50 mg or 100/200 mg, according to patient age and/or weight, given once daily for 3 days (Days 0, 1 and 2). Resulting fixed total dose of AS 75 mg to 600 mg and MQ 150 mg to 1200 mg as per the four age/weight-based dosing groups.

3 days of dosing. Duration of 63 days

251 449 (90.0%) patients presented with at least one TEAE, including 247 (49.5%) patients with drug-related TEAE(s). No significant difference between the two treatment regimens for incidence of patients with at least one TEAE (p=0.0669) or at least one drug-related TEAE (p=0.6883). Most frequently reported drug-related TEAEs were Gastrointestinal Disorders (123 [24.6%] patients). The majority of TEAEs and drug-related TEAEs were mild to moderate and had


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Duration of Study


Key Safety Data

Comparator loose tablets AS and MQ: AS 50 mg tablets (Arsumax®, Sanofi-Aventis, France) and MQ 250 mg tablets (Lariam®, Roche, Basel, Switzerland): Dosing utilised the standard split-dose regimen for co-administration of these agents: AS total dose of 12 mg/kg, given as 4 mg/kg/day for 3 days (Days 0, 1 and 2). Total dose AS 75 mg to 825 mg, based on body weight measured on the first day of treatment MQ total dose of 25 mg/kg given as divided dose 15 mg/kg/day and 10 mg/kg/day on the second and third day of treatment, respectively. Total dose MQ 125 to 1000 mg and 62.5 to 750 mg on the second and third day of treatment, respectively, based on body weight.

resolved by the end of the study. A lower incidence of early vomiting was reported for the ASMQ FDC treatment group. No deaths reported during the study. 10 patients reported 11 serious adverse events: 2 patients in ASMQ FDC group and 8 patients in loose tablets group. 2 patients prematurely discontinued due to repeated vomiting after administration of MQ in loose tablets group. Except for the expected change in the platelet count from Day 0 to Day 28, only minimal changes were observed in the laboratory parameters. The decrease in the proportion of patients with signs and symptoms from Day 0 to Day 7 (post-dosing) was similar for both treatment groups.

• ASMQ FDC Post-Marketing Data

ASMQ FDC tablets have been registered in Brazil; Marketing Authorization was granted by the Brazil ANVISA Health Authority, in March 2008, and to date, over 260.000 treatments that have been purchased or ordered by Brazilian government agencies and and subsequently made available at no cost for field distribution by the Brazilian government. The ANVISA adverse event surveillance system (NOTIVISA) has not notified Farmanguinhos manufacturing site and holder of registration of any serious adverse events or indeed any adverse events to date. In India, 2012, more than 20.000 treatments of ASMQ FDC manufactured by Cipla have been distributed in the private sector of India for the treatment of uncomplicated malaria in adult patients. Pharmacovigilance follow up is assured by Cipla in India and via its agents in other Asian countries.

11.3 Summary of Product Characteristics

11.3.1 Qualitative and quantitative composition

Each artesunate/mefloquine (as hydrochloride) tablets contains 25 mg of artesunate and 50 mg of mefloquine (as 55 mg mefloquine hydrochloride). Each artesunate/mefloquine (as hydrochloride) tablets contains 100 mg of artesunate and 200 mg of mefloquine (as 220 mg mefloquine hydrochloride).


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11.3.2 Pharmaceutical form Artesunate/mefloquine (as hydrochloride) tablets are round, smooth, biconvex, blue coated tablets. Tablet diameters are 6.0 mm and 9.6 mm for the 25mg/50mg and 100mg/200mg tablets, respectively. 11.3.3 Clinical particulars � Therapeutic indications

Artesunate/mefloquine (as hydrochloride) tablets are indicated for the treatment of acute uncomplicated Plasmodium falciparum malaria, resulting either from P. falciparum monoinfection or mixed infections with P. vivax. Although there are no clinical data, there is no reason to suggest that artesunate/mefloquine (as hydrochloride) tablets would not be effective for mixed infections of P. falciparum and P. ovale or P. malariae. � Posology and method of administration

Route of Administration: Oral.

Recommended Dosage: See dosage table in section 9.1. Where accurate weighing scales are available, dosing should be based on weight using the target doses of 4 mg/kg for artesunate and 8 mg/kg for mefloquine. In patients at the extremes of weight for the corresponding age (such as in cases of malnutrition and obesity), the dose should be adjusted according to the weight of the patient. No data in adult patients weighing more than 69 kg has been collected, but artesunate/mefloquine (as hydrochloride) 100mg/200mg tablets may be given daily for 3 days, at the discretion of the physician. If a full treatment course does not lead to improvement within 48 to 72 hours the patient should be re-evaluated. If vomiting occurs within 30 minutes of drug administration, the full daily dose of artesunate/mefloquine (as hydrochloride) tablets should be repeated. If vomiting occurs more than 30 minutes after dosing, half the recommended daily dose of artesunate/mefloquine (as hydrochloride) tablets should be given.

Additional Information on special population: No adjustment of the adult dosage is recommended for elderly patients.

Renal/Hepatic impairment: No adjustment of the adult dosage is recommended for patients with renal impairment, and patients with mild or moderate liver impairment, although data are limited for artesunate and mefloquine either alone or in combination. Pediatric Population: artesunate/mefloquine (as hydrochloride) 25mg/50mg tablets are not recommended for treatment in infants less than 6 months old and/or weighing less than 5 kg. For children who are unable to swallow tablets, the tablet(s) should be placed on a teaspoon containing water and allowed to disintegrate before oral administration: Place an artesunate/mefloquine (as hydrochloride) 25mg/50mg tablets in a teaspoon filled with water, allow to disintegrate for about 3 minutes, shake gently, and administer the contents of the teaspoon to the child. Re-fill the teaspoon with water and administer to the child. Sugar or a sugary food or drink can be administered to help with any unpleasant aftertaste.

� Contraindications: artesunate/mefloquine (as hydrochloride) tablets should not be administered to patients:

• with a known hypersensitivity to mefloquine • with a known hypersensitivity to quinine and quinidine • with a known hypersensitivity to artesunate or other artemisinins


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• with a history of psychiatric illness, including depression, bipolar affective disorder, schizophrenia, severe anxiety neurosis - mefloquine may precipitate or exacerbate these disorders

• with a history of epilepsy - mefloquine may increase the risk of convulsions • in the first trimester of pregnancy • in the recovery of severe malaria, mefloquine has been shown to increase the risk of convulsions • concurrent or recent halofantrine therapy, increased risk of prolongation of the QTc interval • concurrent or recent ketoconazole therapy, increased risk of prolongation of the QTc interval

Falciparum malaria can be a dangerous illness, especially in travelers, young children, pregnant women, and those with no or limited immunity. In cases where diagnosis is not available and where the choice of alternative effective antimalarial drugs is limited, artesunate/mefloquine (as hydrochloride) tablets should not be withheld if the clinician considers that effective antimalarial treatment will be life-saving. � Special warnings and precautions for use: Individuals taking artesunate/mefloquine (as hydrochloride) 25mg/50mg tablets for the treatment of malaria should take a full course of treatment, including extra doses in case of vomiting. Malaria may return despite the use of an effective antimalarial treatment and a good initial clinical response. This can occur if the patient has a late treatment failure (i.e. the parasites reduce in number but are not all killed and then increase in number) or if patients who remain in the malaria endemic region become reinfected. If there is reappearance of clinical symptoms and signs of malaria, patients should be immediately evaluated and, if clinically indicated, effective antimalarial treatment should be prescribed. Artesunate/mefloquine (as hydrochloride) tablets should not be used within two months of a therapeutic dose of mefloquine because of the increased risk of mefloquine induced neuropsychiatric side effects. Caution should be exercised in:

• Patients with underlying cardiac conduction defects or known cardiac arrhythmias: mefloquine at therapeutic or prophylactic doses has a very good cardiac safety record. In rare cases, treatment and prophylaxis with mefloquine have been associated with clinically significant cardiac conduction side-effects. In vitro, mefloquine blocks preferentially the slow (IKs) component of the delayed rectifier potassium (K+) channel in cardiac muscle and, therefore theoretically has the potential to exacerbate the QTc prolongation produced by other drugs. A study of artesunate/mefloquine (as hydrochloride) tablets in patients with malaria reported an increase in QTc interval attributed to slowing of the heart rate in parallel with fever resolution.

• Patients with severe liver impairment as mefloquine undergoes hepatic metabolism

� Interaction with other medicinal products and other forms of interaction: No formal drug-drug interaction studies have been conducted with

artesunate/mefloquine (as hydrochloride) tablets.

Food: There are no food interaction data with the artesunate/mefloquine (as hydrochloride) tablets. Data in P. falciparum-infected patients treated with mefloquine and artesunate given as loose tablets did not indicate any consistent effect of food on mefloquine AUC. Antimalarials: Halofantrine is a potent inhibitor of the rapid (IKr) component of the delayed rectifier K+ channel in cardiac muscle and may cause fatal prolongation of the QTc. This has occurred when halofantrine was used alone or after treating falciparum infected patients who had failed mefloquine treatment. Therefore, artesunate/mefloquine (as hydrochloride) tablets must not be given together with halofantrine or to recent (Within 21 days) halofantrine treatment failures. Co-administration of mefloquine and quinine produced a modest increase in QTc in patients and volunteers that correlated only with quinine


29

concentrations. There has been extensive experience with the use of a quinine loading dose (20 mg salt/kg) for treating severe falciparum malaria in patients treated earlier with mefloquine with no deleterious cardiac effects. In addition, a study in malaria patients did not find a significant cardiac interaction between the quinine (10 mg salt/kg) dose and oral mefloquine (15 mg/kg) given together. Quinidine and chloroquine have been associated with prolongation of the QTc interval. Although there are no interaction data with mefloquine for either drug, an increase in the QTc interval is theoretically possible. Concurrent use of mefloquine with chloroquine or quinine may increase the risk of convulsions. This may also apply to artesunate/mefloquine (as hydrochloride) tablets. Cardiac drugs: A number of cardiac drugs (e.g. quinidine, amiodarone, sotalol, disopyramide) are known to prolong the QTc interval. Therefore, caution is advised when giving artesunate/mefloquine (as hydrochloride) tablets with these drugs, as theoretically there could be an increased risk of QTc prolongation. Treatment of malaria by several antimalarial drugs, including artesunate/mefloquine (as hydrochloride) tablets, results in a slowing of the heart rate because of fever resolution. This effect may be exacerbated in patients who are already taking drugs that reduce the cardiac rate e.g. digoxin, β-blockers, verapamil, diltiazem, ivabradine. Non cardiac drugs producing QTc prolongation: Drugs associated with QTc prolongation include tricyclic antidepressants, phenothiazines, haloperidol, pimozide, terfenadine, astemizole, ketoconazole, moxifloxacin, cisapride, and metoclopramide. Therefore, caution is advised when giving artesunate/mefloquine (as hydrochloride) tablets with these drugs, as theoretically, there could be an increased risk of QTc prolongation. Antimicrobial agents/ketoconazole: mefloquine concentrations are increased by the co-administration with ampicillin and tetracycline. Mefloquine concentrations are reduced with concomitant use with rifampicin. Ketoconazole, an inhibitor of CYP 3A4, results in increase mefloquine concentrations. There has been a report of convulsions in three patients treated with mefloquine combined with the quinolones ciprofloxacin, ofloxacin and sparfloxacin. As noted above, moxifloxacin and ketoconazole are known to induce QTc prolongation in both clinical and preclinical models. Therefore, caution is advised when giving artesunate/mefloquine (as hydrochloride) tablets with either drug because of the theoretical risk of a prolongation of the QTc interval. Anticonvulsants: artesunate/mefloquine (as hydrochloride) tablets should not be given to epileptic patients as mefloquine reduces the plasma levels of anticonvulsants e.g. carbamazepine, phenobarbital, phenytoin, valproic acid. However, if no other choice is available, dose adjustment of anti-seizure medication may be necessary during treatment with artesunate/mefloquine (as hydrochloride) tablets. Metoclopramide: as well as the potential for QTc prolongation, the concurrent use of metoclopramide may increase the plasma concentrations of mefloquine. Antiretrovirals: in vitro studies have shown that antiretroviral agents such as saquanivir and ritonavir can act synergistically with mefloquine to inhibit the development of P. falciparum. There are very limited data on mefloquine and antiretroviral drugs. One study in HIV positive patients showed no interaction between mefloquine and nelfinivir or indinivir. In another study in healthy volunteers, ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on the pharmacokinetics of ritonavir that were not explained by hepatic CYP3A4 activity or ritonavir protein binding. Vaccines: mefloquine may cause an attenuation of the oral live typhoid vaccine (Ty21). Several authorities recommend completion of the oral typhoid vaccine before commencing mefloquine prophylaxis. Time intervals vary up to a maximum of one week. However, treatment with artesunate/mefloquine (as hydrochloride) tablets should not be delayed even if the course of oral typhoid vaccine has not been completed.


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� Pregnancy and lactation: in accordance with the WHO Guidelines for the Treatment of Malaria, the current assessment of benefits compared with potential risks suggests that artesunate/mefloquine (as hydrochloride) tablets may be used in the second and third trimester of pregnancy but should NOT be used in the first trimester until more information becomes available. Mefloquine is secreted into breast milk. Therefore, artesunate/mefloquine (as hydrochloride) tablets should not be given to nursing mothers. Alternatively, breastfeeding should be discontinued during treatment.

� Effect on ability to drive and use machines: mefloquine can cause dizziness and severe vertigo. Patients who experience such side-effects during or after

treatment with artesunate/mefloquine (as hydrochloride) tablets should not drive, operate machinery or perform tasks that require a high degree of manual and/or psychomotor dexterity.

� Undesirable effects: in the pivotal clinical studies of artesunate/mefloquine (as hydrochloride) tablets, about 50% of patients experienced adverse reactions,

which usually occurred within the first 28 days after the start of treatment. The following adverse events were reported during clinical studies in patients with acute, uncomplicated P. falciparum malaria, and were considered at least possibly related to treatment with artesunate/mefloquine (as hydrochloride) tablets.

Frequency Adverse Event

System Organ Class Preferred Term Very common (>1/10 patients)

Gastrointestinal disorders Vomiting Nervous system disorders Dizziness Psychiatric disorders Sleep disorder

Common (>1/100 to < 1/10 patients)

Gastrointestinal disorders Nausea, abdominal pain, diarrhoea Nervous system disorders Headache Metabolism and nutrition disorders Anorexia General disorders and administration site conditions Fatigue Cardiac disorders Palpitations Muskuloeskeletal and connective tissue disorders Myalgia, artharlgia Ear and laberynth disorders Hearing impaired Infections and infestations Recrudescence of malaria Hepatobiliary disorders Hyperbilirrubinaemia

Uncommon (>1/1000 to < 1/100 patients)

Psychiatric disorders Hallucination (visual) Hepatobiliary disorders Hepatitis Eye disorders Blurred vision or other visual disturbance Skin and subcutaneous tissue doisorders Pruritus

Within the medical literature, other adverse events which have been reported to occur with artesunate plus mefloquine combinations include weakness, urticaria, other skin rashes (e.g. erythematous maculapapular rash), rigors, tremor, confusion, numbness. Serious psychiatric adverse events (seizure, depressive syndrome, acute psychosis) and acute intravascular haemolysis with haemoglobinuria were reported rarely. � Overdose: in the event of an overdose the symptoms described in the section of undesirable effects may be more pronounced: cardiac, hepatic and neurological

symptoms have been reported. Patients should be monitored by ECG and observed for neuropsychiatric symptoms for at least 24 hours. Supportive care should be given as clinically indicated.


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11.3.4 Pharmacological properties

� Pharmacodynamic properties

Artesunate: is an artemisinin derivative and its principal metabolite dihydroartemisinin (DHA) are toxic to malaria parasites at nanomolar concentrations. There is enhanced uptake of the drug by red blood cells infected with parasites, which is rapid and saturable. In vitro, artesunate has been shown to have broad specificity acting on all stages of the asexual life cycle of P. falciparum: rings, trophozoites, schizonts and young but not mature gametocytes. The activity of the artemisinins is due to their trioxane pharmacophore but the precise mode of action on the parasitised red blood cell is incompletely understood. Mefloquine: is an antimalarial agent with highly active schizontocide activity but is not gametocidal. It is active against chloroquine-resistant P. falciparum. The exact mechanism of action of mefloquine is unclear but it is has a high affinity for erythrocyte membranes. For the treatment of resistant P. falciparum malaria, the WHO Guidelines for the Treatment of Malaria recommend using a conventional antimalarial such as mefloquine with an artemisinin derivative such as artesunate. Experience with artesunate-mefloquine combinations for treating multidrug resistant P. falciparum malaria in low transmission areas has demonstrated sustained high cure rates of approximately 95%, and good tolerability with very few patients requiring a change of treatment. The efficacy of artesunate/mefloquine (as hydrochloride) tablets will depend on the drug sensitivities of the local malaria parasites. To date, there is evidence of a decline in cure rates of artesunate plus mefloquine given as separate tablets in Western Cambodia and a slowing of parasite clearance in North-Western Thailand. An open-label clinical study in 500 patients (adults and children) in North-Western Thailand reported almost identical cure rates for patients treated with artesunate/mefloquine (as hydrochloride) tablets (91.9%) and a standard dose regimen of artesunate and mefloquine given as separate tablets (89.2%). Parasitological responses were similar across the different age and weight categories although the database was not large enough to allow appropriately powered statistical comparisons. An additional, randomised open-label study in 50 adult patients with acute, uncomplicated P. falciparum malaria conducted in Thailand reported no statistical difference in 28-day parasitological cure rates between patients treated with artesunate/mefloquine (as hydrochloride) tablets (95.8%) and those who received standard dose artesunate and mefloquine administered as separate tablets (100%). An open-label, single-arm study with artesunate/mefloquine (as hydrochloride) tablets in 77 adult patients with acute, uncomplicated P. falciparum malaria conducted in India reported 63-day parasitological cure rates of 100%. � Pharmacokinetic properties Orally administered artesunate is rapidly metabolized to the active metabolite DHA. Artesunate and DHA are absorbed rapidly in the gastrointestinal tract. Bioavailability is high (approximately 50%). Protein binding, mostly to albumin, is reported to be 43% for DHA and 59% for sodium artesunate. DHA is mainly excreted in the urine with less than 1% of unchanged artesunate present in the urine and faeces. Mefloquine is absorbed from the gastrointestinal tract and is widely and rapidly distributed throughout the body. The mean times to maximum concentrations range from 6 to 24 hours in healthy volunteers. Plasma levels are higher in patients with malaria than in healthy volunteers. Mefloquine is 98% bound to plasma proteins and is partly metabolized in the liver by cytochrome P450 isoenzymes to inactive 4-carboxylic acid metabolite, and several other metabolites. Mefloquine has a long half-life of 14- 28 days. Excretion is mainly in the faeces but some unchanged mefloquine (5-13%) may be present in the urine. A study in 24 healthy volunteers investigated the pharmacokinetic properties of artesunate/mefloquine (as hydrochloride) 100mg/200mg tablets. A summary of the PK parameters for artesunate, DHA and mefloquine is presented in the following table:


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Pharmacokinetic parameters of two artesunate/mefloquine (as hydrochloride) 100mg/200mgtablets in Healthy Thai Adult Volunteers

PK Paramether Artesunate (n=23)

Dihydroartemisinin (n=24)

Mefloquine (n=24)

Geometric mean

Cmax (ng/mL) 124.70 630.57 687.14

AUCo-t (ng.h/mL) 105.21 1570.95 304100.00

Mean

Tmax (h) 0.6 1.4 24.0

T½ (h) 0.8 1.8 485.5

� Preclinical safety data: artesunate and mefloquine have been extensively and safely used for many years for the treatment of malaria at doses similar to those used in the artesunate/mefloquine (as hydrochloride) tablets. Artemisinin derivatives, of which artesunate is one, have been associated with neurotoxicity following prolonged exposure to very high doses in animals. To date, there is no convincing clinical evidence of neurotoxicity in treated patients. Furthermore, the potential for neurotoxicity in man is highly unlikely given the rapid clearance of artesunate and short exposure (3 days of treatment). Artemisinins are also known to be embryotoxic and artesunate has been shown to cause increases in post-implantation loss and teratogenicity (low incidence of cardiovascular and skeletal malformations) in rats and rabbits. In rats and mice, mefloquine has been shown to cross the placenta and is teratogenic in early gestation. Mefloquine is also secreted into breast milk.

Preclinical studies with the artesunate/mefloquine (as hydrochloride) tablets did not reveal any new safety concerns.

11.3.5 Pharmaceutical particulars � List of Excipients Core Tablet - Microcrystalline cellulose, croscarmellose sodium, magnesium stearate. Tablet Coating - Opadry Blue YS-1-10571 [contains hypromellose 3cP, hypromellose 6cP, titanium dioxide, polyethylene gycol 400, FD & C blue # 2 (indigo carmine aluminium lake E132), polysorbate 80]. � Incompatibilities: none. � Shelf-Life: 2 years.


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� Special Precautions for Storage: Do not store above 30°C � Nature and Contents of Container Primary packing: Aluminium strips containing 3 tablets Secondary packing: Carton having one strip of 3’s and carton having 2 strips of 3’s, according to age category defined in the Dosage section. � Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the

product: not applicable.

11.4 Summary of comparative safety of artesunate plus mefloquine Fixed-Dose Combination against comparators: The following study represents the first comparison of all currently available fixed-dose artemisinin combination treatments for falciparum malaria, which ratifies the safety profile of ASMQ FDC as described in the section 11.3 (Summary of Product Characteristics) . Study Reference and Objective Total Number of Subjects

Dose and Regimen Duration of Study

Number Patients Receiving ASMQ FDC

Key Safety Data

Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria. 40 An open-label randomized trial to compare the effectiveness of all four WHO-reccommended Fixed-dose ACTs (artesunate–mefloquine, artesunate–amodiaquine, dihydroartemisinin–piperaquine, artemether–lumefantrine) and loose artesunate–mefloquine in Burmese adults and children. The aim was to compare the efficacy of the four available fixed-dose ACTs and the currently used loose tablet combination of artesunate with mefloquine and to assess the effectiveness of adding a single

Of the 808 patients with acute uncomplicated Plasmodium falciparum malaria or mixed infection, 169 were randomly assigned to ASMQ FDC, 161 to AS+MQ loose combination, 155 patients received artesunate–amodiaquine, 162 artemether–lumefantrine, and 161 dihydroartemisinin–piperaquine. 397 of 808 (49,1%) also received primaquine. For the four fixed-dose combinations the standard dosage instructions of the manufacturer for weight and age ranges were followed: ASMQ=25 mg + 55 mg or 100 mg + 220 mg tb, the target dose was 4 mg/kg/D plus 8,8 mg/kg/D/3 D. AL= 20 mg plus 120 mg tablet twice daily for 3 days, the target dose was 3,3 mg/kg/D + 19,8 mg/kg/D; patients were advised to consume some fatty food (or mothers were encouraged to breastfeed treated infants) before each dose. DHA-PQ=40 mg + 320 mg or 20 mg + 160 mg tb, the target dose was 2,5 mg/kg/D + 20 mg/kg/D. ASAQ=25 mg + 67,5 mg, 50 mg + 135 mg, or 100 mg + 270 mg tb, the target dose was 4 mg/kg/D + 10,8 mg base/kg/D.

Dec 2008 to March 2009 Patients were followed up for 63 days.

169 patients on ASMQ Fixed-dose combination (ASMQ FDC) 161 patients on ASMQ Loose combination (AS+MQ L)

599 patients (74%) reported adverse events; 13 patients (1,6%) vomited within the first hour (9 patients within 30 min and 4 within 30–60 min), 4 after AS+MQ L regimen, 3 after ASAQ, 2 after AL, 2 after ASMQ and 2 after DHA-PQ. None vomited again after treatment was repeated. Dizziness was more common after FDC ASMQ than after AL (RR 1・24; 95% CI 1.03–1.48; p=0・03) and DHA-PQ (1.22; 1.02–1.45). Other side-effects were less common and were not related to a specific treatment. The only side-effect attributable to primaquine was abdominal pain. There were no cases of urticaria or other potentially serious skin reactions, convulsions, behavior disturbances, blackwater fever, or severe anemia (<50 g/L).


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Study Reference and Objective Total Number of Subjects Dose and Regimen

Duration of Study

Number Patients Receiving ASMQ FDC

Key Safety Data

gametocytocidal dose of primaquine. Smithuis et al. 2010

AS+MQ loose tb= AS 4 mg/kg/D/3D (total 12 mg/kg)and MQ 25 mg base/kg on day 0. All patients were also randomly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not.

Comments: All ACTs were well tolerated and with exception of ASAQ, all were highly effective, suggesting good adherence to the prescribed treatments, although only the first dose was observed. Although AS+MQ regimens were associated with slightly more dizziness than were AL or DHA-PQ, high cure rates argue against a significant effect on adherence. Patients who received AS+MQ regimens had the lowest rates of gametocyte carriage after treatment, probably because of the higher dose of the artemisinin derivative compared with AL and DHA-PQ.


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11.4.1 Available data of comparative safety of artesunate plus mefloquine as Loose Combination against comparators: There is not a standardized system for generating and analyzing tolerability and safety data from anti-malarial drug studies; often cursorily presented in papers and difficult to summarize. As listed below, several published studies involving artesunate plus mefloquine have reported on its comparative safety and tolerability, with results that are aligned with the safety profile of ASMQ FDC as described in the section 11.3 (Summary of Product Characteristics).

Study Reference, Region and Year of the study Total Number of Subjects Dose and Regimen & Duration of Study

Randomized comparison of artemether-benflumetol and artesunate mefloquine in treatment of multidrug-resistant falciparum malaria.35Thailand 1995 to 1996

Artemether-benflumetol (Novartis) and artesunate-mefloquine as AS (Guilin) plus MQ (Hoffman-La Roche) Artemether-benflumetol: 309 patients Artesunate mefloquine: 308 patients 63 D Follow up

Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria.36 Thailand 1997 to 1998

Artemether-lumefantrine (Novartis) and artesunate-mefloquine as AS (Guilin) plus mefloquine (Hoffman-La Roche) Artemether-lumefantrine: 150 patients Artesunate mefloquine: 50 patients

28 D follow up

A clinical and pharmacokinetic trial of six doses of artemether/lumefantrine for multidrug-resistant P.falciparum malaria in Thailand.37 1998 to 1999

Artemether-lumefantrine (Novartis) and artesunate-mefloquine (Guilin) Artemether-lumefantrine: 164 patients Artesunate mefloquine: 55 patients

29 D follow up

Dihydroartemisinin-piperaquine against multidrug-resistant P. falciparum malaria in Vietnam: randomized clinical trial54 2001

Dihydroartemisinin-piperaquine (Holleykin), artesunate-mefloquine as AS (Guilin) plus MQ(Hoffman-La Roche) and dihydroartemisinin- trimethoprim- piperaquine (DHA-TP- Tonghe Pharmaceutical, China) Dihydroartemisinin-piperaquine: 166 patients Artesunate mefloquine: 38 & 77 patients DHA-TP: 74 + 157 patients 63 D follow up

A randomized trial of artemether-lumefantrine vs. mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant P. falciparum on the western border of Thailand 2005 38 2001 to 2002

Artemether-lumefantrine (Novartis) and artesunate-mefloquine, as AS (Guilin) plus MQ (Hoffman-La Roche) Artemether-lumefantrine: 245 Artesunate mefloquine: 245 patients 42 D follow up

Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant

Dihydroartemisinin-piperaquine (Holleykin), dihydroartemisinin-piperaquine plus artesunate as DHA-PQ (Holleykin) + AS (Cotec) and artesunate-mefloquine as AS (Guilin)


36


falciparum malaria in Thailand 48 2002 to 2003

plus MQ (Atlantic Laboratories) Dihydroartemisinin-piperaquine: 471 patients Artesunate mefloquine: 176+59=235 patients 28 D follow up=59x3=177 patients 63 D follow up=176+179+174=529 patients

Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine vs. artesunate plus mefloquine vs. artemether-lumefantrine in the treatment of uncomplicated falciparum malaria in the Lao People’s Democratic Republic 41 2002 to 2003

Artemether-lumefantrine (Novartis), artesunate-mefloquine as AS (Guilin) plus MQ (Roche) and chloroquine sulfate (Government Pharmaceutical Organization, Thailand) plus sulfadoxine-pyrimethamine (Roche). Artemether-lumefantrine: 330 patients Artesunate mefloquine: 110 patients CQ + SP : 110 patients 42 D follow up

A randomized open study to assess the efficacy and tolerability of dihydroartemisinin - piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia 50 2002 to 2003

Dihydroartemisinin–piperaquine (Holleykin) and artesunate-mefloquine as AS (Guillin) plus MQ (Mepha) Dihydroartemisinin-piperaquine: 193 patients Artesunate mefloquine: 195 patients 63 D follow up

Efficacy of chloroquine + sulfadoxine-pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh 43 2003

Artemether-lumefantrine (Novartis), artesunate-mefloquine (Manufacturer non specified) and CQ + SP (Manufacturer non specified) Artemether-lumefantrine: 121 patients Artesunate mefloquine: 121 patients CQ + SP : 122 patients 42 D follow up

Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated P. falciparum malaria in Luang Namtha Province, Lao People’s Democratic Republic 42 2003

Artemether-lumefantrine (Novartis) and artesunate-mefloquine, as AS (Mepha) plus MQ (Mepha) Artemether-lumefantrine: 47 patients Artesunate mefloquine: 53 patients 42 D follow up

A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug- resistant falciparum malaria in Thailand 20 2003 to 2004

Dihydroartemisinin-piperaquine (Holleykin) and artesunate-mefloquine as AS (Guilin) and MQ (Atlantic Laboratories) Dihydroartemisinin-piperaquine: 331 patients Artesunate mefloquine: 166 patients 63 D follow up


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Efficacy and effectiveness of dihydroartemisinin-piperaquine vs. artesunate-mefloquine in falciparum malaria: an open-label randomized comparison in Myanmar 51 2003 to 2004

Dihydroartemisinin- piperaquine (Holleykin) and artesunate-mefloquine as AS (Guilin) plus MQ (Hoffman-La Roche) Dihydroartemisinin-piperaquine: 156 supervised + 171 not supervised = 327 Artesunate mefloquine : 162 supervised + 163 not supervised =325 42 D follow up

Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated P. falciparum malaria in Senegal 44 2003 to 2004

Artesunate-amodiaquine (sanofi-aventis), artemether-lumefantrine (Novartis), amodiaquine-SP (Pharmacie Nationale d’Approvion su Sénégal) and artesunate-mefloquine (Mepha) Artesunate-amodiaquine: 360 patients Artemether-lumefantrine: 140 patients Amodiaquine-SP: 161 patients Artesunate-mefloquine: 145 patients 42 D follow up

A randomized controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru 55 2003 to 2005

Artesunate-mefloquine as AS (Guilin) plus MQ (Hoffman-La Roche) and dihydroartemisinin-piperaquine (Holleykin) Dihydroartemisinin-piperaquine: 262 patients Artesunate mefloquine: 260 patients 63 D follow up

An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin–piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People’s Democratic Republic (Laos) 52 2004

Artesunate-mefloquine as AS (Guilin) plus MQ (Roche) and dihydroartemisinin-piperaquine (Holleykin) Dihydroartemisinin-piperaquine: 105 patients Artesunate mefloquine: =107 patients 42 D follow up

A randomized trial of artesunate-mefloquine vs. artemether-lumefantrine for treatment of uncomplicated P. falciparum malaria in Mali 45

2004 to 2005

Artemether-lumefantrine (Novartis) and artesunate-mefloquine (Mepha) Artemether-lumefantrine: 232 patients Artesunate-mefloquine: 232 patients 28 D follow up

Dose ranging studies of new artemisinin-piperaquine fixed combinations compared to standard regimens of artemisinin combination therapies for acute uncomplicated falciparum malaria in Thailand. 81

Artemether-lumefantrine (Novartis), dihydroartemisinin-piperaquine (Holleykin), artesunate-mefloquine (manufacturer non specified) and artemisinin-piperaquine (Artepharm, China) Artemether-lumefantrine : 81 patients


38


2005

Dihydroartemisinin-piperaquine : 82 patients Artesunate-mefloquine: 25 patients Artemisinin-piperaquine : 169 28 D follow up

An open-label, randomised study of dihydroartemisinin-piperaquine vs. artesunate-mefloquine for falciparum malaria in Asia (Thailand, Laos and India)49 2005 to 2007

Dihydroartemisinin-piperaquine (Sigma-Tau) and artesunate-mefloquine (Mepha) Dihydroartemisinin-piperaquine: 767 patients Artesunate mefloquine: 381 patients 63 D follow up

Efficacy of Aretquick® vs. artesunate mefloquine in the treatment of uncomplicated falciparum malaria in Thailand82 2006 to 2007

Artemisinin-piperaquine-primaquine (Artepharm, China) and artesunate-mefloquine (Mepha) Artemisinin-piperaquine-primaquine: 65 patients Artesunate-mefloquine: 65 patients 28 D follow up

Artesunate/mefloquine paediatric formulation vs. artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua kouté, Côte d'Ivoire 46 2007

Artemether lumefantrine (Novartis) and artesunate-mefloquine (Mepha) Artemether-lumefantrine : 75 patients Artesunate-mefloquine: 75 patients 28 D follow up

Randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombia patients with uncomplicated Plasmodium falciparum malaria.47 2007-2008

Artemether-Lumefantrine (Novartis), artesunate plus mefloquine (Mepha) and atovaquone-proguanil (GSK) Artemether-lumefantrine : 159 patients Artesunate-mefloquine: 53 patients Atovaquone-Proguanil: 53 patients 42 D follow up

Pyronaridine-artesunate vs. mefloquine plus artesunate for malaria.56Thailand, Cambodia, Vietnam, India, Burkina Faso, Tanzania & Côte d’Ivoire 2007-2008

Pyronaridine–artesunate (Shin Poong) and artesunate-mefloquine (Mepha) Pyronaridine–artesunate: 846 patients Artesunate –Mefloquine: 423 patients 28 D follow up

A randomized trial of artesunate mefloquine vs. artemether lumefantrine for the treatment of uncomplicated P. falciparum malaria in Senegalese children26 2008

Artemether lumefantrine (Novartis) and artesunate-mefloquine (Mepha) Artemether-lumefantrine: 155 patients Artesunate-mefloquine: 154 patients 28 D follow up


39

12. Summary of available data on comparative cost and cost effectiveness within the pharmacological class or therapeutic group:

The cost of API represents a large part of the final drug product price. To our knowledge, no studies on comparative cost and cost-effectiveness of ASMQ FDC have been conducted within the pharmacological class or therapeutic group. Mefloquine production process is expensive, as it is well known that TDR worked during the 80’s with Hoffman-La Roche, to find a less expensive route to synthesize mefloquine83 before sponsoring more than 12 clinical research studies in Latin America, Zambia and Thailand, leading to product registration. In addition, the price of artemisinin is volatile and artemisinin production represents a significant proportion of the manufacturing cost of ACTs. Current best competitive price per children and adult treatment of ASMQ FDC ranges between 1,22 and 3 U$D and compares well with co-blisters or separate tablets of AS+MQ combination pricing.84 DNDi and its partners are working towards lowering the price of ASMQ in the future. MMV has led a collaborative effort to develop a low cost process for MQ,85 together with Development Chemicals Ltd, a UK-based chemistry team. This process needs to be industrialized. The development of a semisynthetic artemesinin, prepared from a Dihydroartemisinic acid (DHAA) precursor synthesized by Saccharomyces cerevisiae, will be at the lower end of the artesunate pricing band, so ensuring availability at an optimized cost.86-87 Additional characteristics of ASMQ FDC, towards supporting cost-effectiveness of the product:

� With specific presentations for children of ages between 6 months and 11 years and no need to time the doses with food, ASMQ FDC addresses the needs of children, the primary victims of malaria worldwide, at all levels of the health care system, at the community and private sector.

� The Fixed-Dose Combination [both active drugs are taken together] greatly contributes to protect the artemisinin class of drugs � The demonstrated comparative superiority of ASMQ regimens lowering rates of gametocyte carriage after treatment is predicted to have the greatest impact on

transmission across all areas in the short-term time scale.

13. Summary of regulatory status of medicines

ASMQ FDC is pre-qualified by WHO since September 2012.32 Artesunate and mefloquine (ASMQ) Fixed Dose Combination (FDC) tablets 25 / 55 mg and 100 / 220 mg were granted Brazilian registration approval on March 3, 2008; in India on November 30, 2011; in Malaysia on March 29, 2012 and in Myanmar on September 2, 2012. Because Malaysia is a PIC/S (Pharmaceutical Inspection Convention Scheme) member, the approval by the Malaysian Ministry of Health’s National Pharmaceutical Control Bureau for the treatment of acute uncomplicated malaria resulting from Plasmodium falciparum mono infections or from mixed P. falciparum and P. vivax infections is a major step towards further registration of ASMQ FDC in the region, within the ASEAN Pharmaceutical Harmonization Scheme.


40

Artesunate and mefloquine (ASMQ) Fixed Dose Combination (FDC) tablets 25 / 55 mg and 100 / 220 mg is being submitted for registration in the countries where AS+MQ is part of the National Malaria Policy10 and in countries where ASMQ FDC tablets 25 / 55 mg and 100 / 220 mg tablets could be of benefit to patients suffering uncomplicated malaria.

14. Availability of pharmacopoeial standards

Artesunate standards: - WHO (International Pharmacopoeia, Volume X, 4th edition, 2006), - Chinese and Vietnamese Pharmacopoeia. - In house Standard according to the International and the European Pharmacopoeias. Mefloquine (as hydrochloride) standards: - WHO (International Pharmacopoeia, Volume X, 4th edition, 2006), - European Pharmacopoeia: (Ph. Eur) monograph no. 1241 for mefloquine HCl

15. Proposed text for WHO Model Formulary

6.5.3 Antimalarial medicines

6.5.3.1 For curative treatment

ARTESUNATE and MEFLOQUINE (ASMQ) Fixed Dose Combination (FDC) TABLETS 25 / 55 mg

ARTESUNATE and MEFLOQUINE (ASMQ) Fixed Dose Combination (FDC) TABLETS 100 / 220 mg


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Appendix 1: References for clinical data on the use of artesunate (AS) and mefloquine (MQ) co-administration as loose tablets combination or as FDC South East Asia 31 studies in Thailand: 1. Karbwang J, Na Bangchang K, Thanavibul A, Back DJ, Bunnag D, Harinasuta T. Pharmacokinetics of mefloquine alone or in combination with artesunate. Thailand. Bull World Health Organ.

1994;72(1):83-7. 2. Price RN, Nosten F, Luxemburger C, van Vugt M, Phaipun L, et al. (1997). Artesunate/mefloquine treatment of multi-drug resistant falciparum malaria. Thai-Burmese border. Trans R Soc

Trop Med Hyg 91: 574–577. (Report 4 studies) 3. van Vugt M, Brockman A, Gemperli B, Luxemburger C, Gathmann I, et al. (1998) Randomized comparison of artemether-benflumetol and artesunate mefloquine in treatment of multidrug-

resistant falciparum malaria. Thailand.Antimicrob Agents Chemother 42: 135–139. 4. Price RN, Luxemburger C, van Vugt M, Nosten F, Kham A, Simpson J, Looareesuwan S, Chongsuphajaisiddhi T and White NJ. Artesunate and mefloquine in the treatment of uncomplicated

multidrug-resistant hyperparasitaemic falciparum malaria. Thailand. Trans R Soc Trop Med Hyg. 1998 92, 207-211 5. Sabchareon A, Attanath P, Chanthavanich P, Phanuaksook P, Prarinyanupharb V, Poonpanich Y, Mookmanee D, Teja-Isavadharm P, Heppner DG, Brewer TG and Chongsuphajaisiddhi.

Comparative clinical trial of artesunate suppositories and oral artesunate in combination with mefloquine in the treatment of children with acute falciparum malaria. Thailand. Am. J. Trop. Med. Hyg., 58(1), 1998, pp. 11–16

6. van Vugt M, Looareesuwan S, Wilairatana P, McGready R, Villegas L, et al. (2000) Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria. Thailand. Trans R Soc Trop Med Hyg 94: 545–548.

7. McGready R, Brockman A, Cho Thein, Cho D, van Vugt M, Luxemburger C, Chongsuphajaisiddhi, White N and Nosten F. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy. Thailand.Transactions of the Royal Society of tropical Medicine and Hygiene (2000)94,689-69

8. Lefèvre G, Looareesuwan S,Treeprasertsuk S, Krudsood S, Silachamroon U, Gathmann I, Mull R, Bakshi R: A clinical and pharmacokinetic trial of six doses of artemether/lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand. Am J Trop Med Hyg 2001, 64:247-256.

9. van Vugt M, Leonardi E, Phaipun L, Slight T, Thway KL, et al. (2002) Treatment of uncomplicated multidrug-resistant falciparum malaria with artesunate-atovaquone-proguanil. Thailand. Clin Infect Dis 35: 1498–1504.

10. Krudsood S, Looareesuwan S, Silachamroon U, Chalermrut K, Pittrow D, Cambon N, Mueller EA. Artesunate and mefloquine given simultaneously for three days via a prepacked blister is equally effective and tolerated as a standard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand. Am J Trop Med Hyg. 2002 Nov;67(5):465-72.

11. Rojanawatsirivej C,Vijaykadga S,Amklad I,Wilairatna P, Looareesuwan S. Monitoring the therapeutic efficacy of antimalarials against uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health 2003, 34:536-541.

12. Suputtamongkol Y, Chindarat S, Silpasakorn S, Chaikachonpatd S, Lim K, Chanthapakajee K, Kaewkaukul N, Thamlikitkul V. The efficacy of combined mefloquine-artesunate versus mefloquine-primaquine on subsequent development of Plasmodium falciparum gametocytemia. Thailand. Am J Trop Med Hyg. 2003 May;68(5):620-3.

13. Ashley EA, Krudsood S, Phaiphun L, Srivilairit S, McGready R, et al. (2004) Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis 190: 1773–1782.

14. Hutagalung R, Paiphun L, Ashley EA, McGready R, Brockman A, et al. (2005) A randomized trial of artemether-lumefantrine versus mefloquine-artesunate for the treatment of uncomplicated multi-drug resistant Plasmodium falciparum on the western border of Thailand. Malar J 4: 46.

15. Ashley EA, McGready R, Hutagalung R, Phaiphun L, Slight T, et al. (2005) A Randomized, Controlled Study of a Simple, Once-Daily Regimen of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated, Multidrug-Resistant Falciparum Malaria. Thailand.Clin Infect Dis 41: 425–432.

16. Silachamroon U, Krudsood S, Thanachartwet W, Tangpukdee N, Leowattana W, Chalermrut K, Srivilairit S, Wilaiaratana P, Thimasarn K, Looareesuwan S. An open, randomized trial of three-day treatment with artesunate combined with a standard dose of mefloquine divided over either two or three days, for acute, uncomplicated falciparum malaria. Thailand. Southeast Asian J Trop Med Public Health. 2005 May;36(3):591-6.

17. Vijaykadga S, Rojanawatsirivej C, Cholpol S, PhoungmaneeD, Nakavej A and Wongsrichanalai C. In vivo sensitivity monitoring of mefloquine monotherapy and artesunate–mefloquine combinations for the treatment of uncomplicated falciparum malaria in Thailand in 2003. Tropical Medicine and International Health volume 11 no 2 pp 211–219 february 2006

18. Ashley EA, Lwin KM, McGready R, Simon WH, Phaiphun L, et al. (2006) A randomised comparative study of a new fixed combination of mefloquine artesunate compared to the separate drugs for the treatment of uncomplicated multidrug resistant falciparum malaria in Thailand. Trop Med Int Health 11: 1653–1660


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19. Krudsood S, Tangpukdee N, Thanchatwet V, Wilairatana P, Srivilairit S, Pothipak N, Jianping S, Guoqiao L, Brittenham GM, Looareesuwan S. Dose ranging studies of new artemisinin-piperaquine fixed combinations compared to standard regimens of artemisisnin combination therapies for acute uncomplicated falciparum malaria. Thailand. Southeast Asian J Trop Med Public Health. 2007 Nov;38(6):971-8.

20. Tangpukdee N, Krudsood S, Thanachartwet V, Pengruksa C, Phophak N, Kano S, Li G, Brittenham GM, Looareesuwan S. Wilairatana P. Efficacy of Artequick versus artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health. 2008 Jan;39(1):1-8.

21. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald PI, Silamut KI, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NPJ, Lindegardh N, Socheat D and White N. Artemisinin Resistance in Plasmodium falciparum Malaria in Cambodia Thai-Cambodian border. N Engl J Med 2009;361:455-67.

22. Ambler MT, Dubowitz LM, Arunjerdja R, Hla EP, Thwai KL, Viladpainguen J, Singhasivanon P, Luxemburger C, Nosten F, McGready R. The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria. Thailand. Malar J. 2009 Sep 2;8:207.

23. Valecha N, Phyo AP, Mayxay M, Newton PN, Krudsood S, et al. (2010) An Open-Label, Randomised Study of Dihydroartemisinin-Piperaquine Versus Artesunate-Mefloquine for Falciparum Malaria in Asia. PLoS ONE 5(7): e11880. doi:10.1371/journal.pone.0011880

24. Congpuong K, Bualombai P, Banmairuroi V, Na-Bangchang K. Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria. Thailand. Malar J. 2010 Feb 4;9:43.

25. Na-Bangchang K, Ruengweerayut R, Mahamad P, Ruengweerayut K, Chaijaroenkul W. Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar J. 2010 Oct 8;9:273.

26. Krudsood S Looareesuwan S, Tangpukdee N, Wilairatama P, Phumratanaprapin W, Leowattana W, Chalermrut K, Ramanathan S, Navaratnam V, Olliaro P, Vaillant M, Kiechel JR, Taylor WRJ. New fixed dose artesunate/mefloquine for treating multidrug resistant Plasmodium falciparum in adults – a comparative phase IIb safety and pharmacokinetic study with standard dose non-fixed artesunate plus mefloquine, Thailand. Antimicrobial Agents and Chemotherapy, Sept. 2010, p. 3730–3737.

27. Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, PénaliLK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS and Fleckenstein L for the Pyronaridine–Artesunate Study Team. Pyronaridine–Artesunate versus Mefloquine plus Artesunate for Malaria. N Engl J Med. 2012, Apr 5; 366 (14):1298-309. Thailand, Cambodia, Vietnam, Burkina Faso, Ivory Coast, Tanzania & India.

28. Satimai W, Sudathip P, Vijakadge S, Khamsiriwatchara A, Sawang S, Potithavoranan T, Sangvichean A, Delacolette Ch, Singhasivanon P, Kaewkungwal J and Lawpoolsri S. Artemisinin resistance containment project in Thailand. II: responses to mefloquine-artesunate combination therapy among falciparum malaria patients in Thai provinces bordering Cambodia. Malaria Journal 2012,11:300

4 studies in Myanmar: 1. Smithuis F, van der Broek I, Katterman N, Kyaw MK, Brockman A, Lwin S, White NJ. Optimising operational use of artesunate-mefloquine: a randomised comparison of four treatment regimens. Myanmar. Trans R Soc Trop Med Hyg. 2004 Mar;98(3):182-92. 2. Smithuis F, Shahmanesh M, Kyaw MK, Savran O, Lwin S, White NJ. Comparison of chloroquine, sulfadoxine/pyrimethamine, mefloquine and mefloquine-artesunate for the treatment of falciparum malaria in Kachin State, North Myanmar. Trop Med Int Health. 2004 Nov;9(11):1184-90. 3. Smithuis F, Kyaw Kyaw M, Phe O, Zarli Aye K, Htet L, Barends M, Lindegardh N, Singtoroj T, Ashley E, Lwin S, Stepniewska K, White NJ. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison- Myanmar - Lancet 2006; 367: 2075–85. 4. Smithuis F, Moe Kyaw Kyaw, Ohn Phe, Thein Win, Pyay Phyo Aung, Aung Pyay Phyo Oo, Arkar Linn Naing, Mya Yee Nyo,Naing Zaw Htun Myint, Mallika Imwong,Ashley E, Lee SJ, White N. Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. Myanmar. Lancet Infect Dis. 2010 Oct;10(10):673-81. 3 studies in India: 1. Valecha N, Phyo AP, Mayxay M, Newton PN, Krudsood S, et al. (2010) An Open-Label, Randomised Study of Dihydroartemisinin Piperaquine Versus Artesunate-Mefloquine for Falciparum Malaria in Asia. PLoS ONE 5(7): e11880. doi:10.1371/journal.pone.0011880 2. Campbell P, Baruah S, Narain K, Rogers CC. A randomized trial comparing the efficacy of four treatment regimens for uncomplicated falciparum malaria in Assam state, India. Trans R Soc Trop Med Hyg. 2006 Feb;100(2):108-18. 3. Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, PénaliLK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS and Fleckenstein L for the Pyronaridine–Artesunate Study Team. Pyronaridine–Artesunate versus Mefloquine plus Artesunate for Malaria. N Engl J Med. 2012, Apr 5; 366 (14):1298-309. Thailand, Cambodia, Vietnam, Burkina


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Faso, Ivory Coast, Tanzania & India. 1 study in Bangladesh: van den Broek IV, Maung UA, Peters A, Liem L, Kamal M, Rahman M, Rahman MR, Bangali AM, Das S, Barends M, Faiz AM: Efficacy of chloroquine + sulfadoxine-pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh. Trans R Soc Trop Med Hyg 2005, 99:727-735. Western Pacific 19 studies in Cambodia: 1. Denis MB, Tsuyuoka R, Poravuth Y, Narann TS, Seila S, Lim C, Incardona S, Lim P, Sem R, Socheat D, Christophel EM, Ringwald P. Surveillance of the efficacy of artesunate and mefloquine combination for the treatment of uncomplicated falciparum malaria in Cambodia. Tropical Medicine and International Health. 2006 Sep; 11(9): 1360-6. (Report 14 studies) 2. Rogers WO, Sem R, Tero T, Chim P, Lim P, Muth S, Socheat D, Ariey F and Wongsrichanalai C. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia- Malaria Journal 2009, 8:10 3. Denis MB, Tsuyuoka R, Lim P, Lindegardh N, Yi P, Top SN, Socheat D, Fandeur T, Annerberg A, Christophel EM, Ringwald P. Efficacy of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in northwest Cambodia. Tropical Medicine and International Health. 2006 Dec; 11(12): 1800-7. 4. Janssens B, van Herp M, Goubert L, Chan S, Uong S, Nong S, Socheat D, Brockman A, Ashley EA and Van Damme W. A randomized open study to assess the efficacy and tolerability of dihydroartemisinin–piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia. Tropical Medicine and International Health- volume 12 no 2 pp 251–259 - 2007. 5. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald PI, Silamut KI, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NPJ, Lindegardh N, Socheat D and White N. Artemisinin Resistance in Plasmodium falciparum Malaria in Cambodia. N Engl J Med 2009;361:455-67. 6. Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, PénaliLK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS and Fleckenstein L for the Pyronaridine–Artesunate Study Team. Pyronaridine–Artesunate versus Mefloquine plus Artesunate for Malaria. N Engl J Med. 2012, Apr 5; 366 (14):1298-309. Thailand, Cambodia, Vietnam, Burkina Faso, Ivory Coast, Tanzania & India. 4 studies in Laos: 1. Mayxay M, Khanthavong M, Lindegårdh N, Keola S, Barends M, Pongvongsa T, Yapom R, Annerberg A, Phompida S, Phetsouvanh R, White NJ,Newton PN:Randomized comparison of chloroquine plus sulfadoxine-pyrimethamine versus artesunate plus mefloquine versus artemether/lumefantrine in the treatment of uncomplicated falciparum malaria in the Lao People’s Democratic Republic. Clin Infect Dis 2004, 39:1139-1147. 2. Stohrer JM, Dittrich S, Thongpaseuth V, Vanisaveth V, Phetsouvanh R, Phompida S, Monti F, Christophel EM, Lindegardh N, Annerberg A, Jelinek T.Therapeutic efficacy of artemether-lumefantrine and artesunate-mefloquine for treatment of uncomplicated Plasmodium falciparum malaria in Luang Namtha Province, Lao People's Democratic Republic. Trop Med Int Health. 2004 Nov;9(11):1175-83. 3. Mayxay M, Thongpraseuth V, Khanthavong M, Lindegardh N, Barends M, Keola S, Pongvongsa T, Phompida S, Phetsouvanh R, Stepniewska K, White N. J. and Newton P. N. An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin–piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People’s Democratic Republic (Laos). Tropical Medicine and International Health- volume 11 no 8 pp 1–9 august 2006. 4. Mayxay M, Keomany S, Khanthavong M, Souvannasing P, Stepniewska K, Khomthilath T, Keola S, Pongvongsa T, Phompida S, Ubben D, Valecha Neena, White NJ and Newton PN. A phase III, randomized, non-inferiority trial to assess efficacy and safety of dihydroartemisinin-piperaquine in comparison with artesunate-mefloquine in patients with uncomplicated Plasmodium falciparum malaria in Southern Laos. Am. J. Trop. Med. Hyg. 83 (6), 2010, pp.1221-1229. (Also reported by Valecha 2010 in PLoS) 3 studies in Vietnam: 1. Hien T T, Dolecek C, Phuong Mai P, Thi Dung N, Thanh Truong N, Hong Thai L, Thi Hoai An D, Tan Thanh T, Stepniewska K, White NJ, Farrar J. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 2004; 363: 18–22. 2. Hung le Q, de Vries PJ, Binh TQ, Giao PT, Nam NV, Holman R, Kager PA. Artesunate with mefloquine at various intervals for non-severe Plasmodium falciparum malaria. Vietnam. Am J Trop Med Hyg. 2004 Aug;71(2):160-6. 3. Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, PénaliLK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS and Fleckenstein L for the Pyronaridine–Artesunate Study Team. Pyronaridine–Artesunate versus Mefloquine plus Artesunate for Malaria. N Engl J Med. 2012, Apr 5; 366 (14):1298-309. Thailand, Cambodia, Vietnam, Burkina Faso, Ivory Coast, Tanzania & India.


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Latin America 5 studies in Peru: 1. Pillai DR, Hijar G, Montoya Y, Marouiño W, Ruebush TK 2nd, Wongsrichanalai C, Kain KC. Lack of prediction of mefloquine and mefloquine-artesunate treatment outcome by mutations in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene for P. falciparum malaria in Peru. Am J Trop Med Hyg. 2003 Jan;68(1):107-10. 2. Grande T, Bernasconi A, Erhart A, Gamboa D, Casapia M, Delgado C, Torres K, Fanello C, Llanos-Cuentas A, D'Alessandro U. A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru. PLoS One. 2007 Oct 31;2(10):e1101. 3. Marquiño W, Huilca M, Calampa C, Falconí E, Cabezas C, Naupay R, Ruebush TK 2nd. Efficacy of mefloquine and a mefloquine-artesunate combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon Basin of Peru. Am J Trop Med Hyg. 2003 May;68(5):608-12. 4. Gutman J , Green M , Durand S , Rojas OV , Ganguly B , Quezada WM , Utz GC , Slutsker L , Ruebush TK II , Bacon DJ. Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria . Malar J 2009 8: 58 . 5. Macedo de Oliveira A, Chavez J , Ponce de Leon G , Durand S , Arrospide N, Roberts J, Cabezas C and Marquiño W. Efficacy and Effectiveness of Mefloquine and Artesunate Combination Therapy for Uncomplicated Plasmodium falciparum Malaria in the Peruvian Amazon. Am. J. Trop. Med. Hyg., 85(3), 2011, pp. 573–578 2 studies in Colombia: 1. Alvarez G, Tobón A, Piñeiros JG, Ríos A and Blair S. Dynamics of Plasmodium falciparum Parasitemia Regarding Combined Treatment- Regimens for Acute Uncomplicated Malaria, Antioquia, Colombia. Am. J. Trop. Med. Hyg., 83(1), 2010, pp. 90–96 2. Carrasquilla G, Barón C, Monsell EM, Cousin M, Walter V, Levèvre G, Sander O and Fisher LM. Randomized, prospective, three-arm study to confirm the auditory safety an efficacy of artemether-lumefantribe in Colombia patients with uncomplicated Plasmodium falciparum malaria. Am. J. Trop. Med. Hyg., 86(1), 2012,pp75-83 1 study in Bolivia Avila JC, Villaroel R, Marquiño W, Zegarra J, Mollinedo R, Ruebush TK. Efficacy of mefloquine and mefloquine-artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in the Amazon region of Bolivia. Trop Med Int Health. 2004 Feb;9(2):217-21. 1 study in Ecuador: Gomez L EA, Jurado MH, Cambon N. Randomised efficacy and safety study of two 3-day artesunate rectal capsule/mefloquine regimens versus artesunate alone for uncomplicated malaria in Ecuadorian children. Acta Tropica 89 (2003) 47–53 1 study in Brazil: Santelli AC, Ribeiro I, Daher A, Boulos M, Marchesini PB, dos Santos RlC, Lucena MBF, Magalhaes I, Leon AP, Junger W, Ladislau JL: Effect of artesunate-mefloquine fixed-dose combination in malaria transmission in amazon basin communities. Malar J 2012, 11. Africa 3 studies in Nigeria: 1. Sowunmi A, Gbotosho GO, Happi C, Okuboyejo T, Folarin O, Balogun S, Michael O.Therapeutic efficacy and effects of artesunate-mefloquine and mefloquine alone on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria.Am J Trop Med Hyg. 2009 Dec;81(6):979-86. 2. Agomo PU, Meremikwu MM, Watila IM, Omalu IJ, Odey FA, Oguche S, Ezeiru VI, Aina OO. Efficacy, safety and tolerability of artesunate-mefloquine in the treatment of uncomplicated Plasmodium falciparum malaria in four geographic zones of Nigeria. Malar J. 2008 Sep 9;7:172. 3. Sowunmi A, Oduola AMJ, Ogundahunsi OAT, Fehintola FA, Ilesanmi OA, Akinyinka OO, Arowojolu AO. Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy. Nigeria. Journal of Obstetrics & Gynaecology; Jul98, Vol. 18 Issue 4, p322-327 2 studies in Senegal: 1. Faye B, Ndiaye JL, Ndiaye D, Dieng Y, Faye O and Gaye O. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated P falciparum malaria in Senegal. Malaria Journal 2007, 6: 80


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2. Faye B, Ndiaye JL, Tine R, Sylla K, Gueye A, Lô AC, Gaye O. A randomized trial of artesunate mefloquine versus artemether lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Senegalese children. Am J Trop Med Hyg. 2010 Jan;82(1):140-4. 2 studies in Gabon: 1. Bouyou-Akotet MK, Ramharter M, Ngoungou EB, Mamfoumbi MM,Mihindou MP, Missinou MA, Kurth F, Bélard S, Agnandji ST, Issifou S, Heidecker JL, Trapp S, Kremsner PG and Kombila M.Efficacy and safety of a new pediatric artesunate mefloquine drug formulation for the treatment of uncomplicated falciparum malaria in Gabon. Wien Klin Wochenschr (2010) 122: 173–178 2. Ramharter M, Kurth FM, Bélard S, Bouyou-Akotet MK, Mamfoumbi MM, Agnandji ST, Missinou MA, Adegnika AA, Issifou S, Cambon N, Heidecker JL, Kombila M, Kremsner PG. Pharmacokinetics of two paediatric artesunate mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon. J Antimicrob Chemother. 2007 Nov;60(5):1091-6. 2 studies in Sudan: 1. Adam, I.1; A-Elbasit, I.E.; Elbashir, M.I. Efficacies of mefloquine alone and of artesunate followed by mefloquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan. Annals of Tropical Medicine and Parasitology, Volume 99, Number 2, March 2005 , pp. 111-117(7) 2. Awad MI, Alkadru AMY, Behrens RH, Baraka OZ and Eltayeb IB. Descriptive study on the efficacy and safety of Artesunate suppository in combination with othe antimalarials in the treatment of severe malaria in Sudan. Am. J. Trop. Med. Hyg., 68(2), 2003, pp. 153–158 2 studies in Cameroon: 1. Whegang SY, Tahar R, Foumane VN, Soula G, Gwét H, Thalabard JC, Basco LK. Efficacy of non-artemisinin- and artemisinin-based combination therapies for uncomplicated falciparum malaria in Cameroon. Malar J. 2010 Feb 19;9:56. 2. Tietche F, Chelo D, Kinkela N, Ntoto M, Minjiwa Djoukoue F, Hatz C, Frey S, Frentzel A, Trapp S, Zielonka R and Mueller E. Tolerability and efficacy of a Pediatric Granule Formulation of Artesunte-Mefloquine in young children from Cameroon with uncomplicated falciparum malaria. Am.J. Trop. Med. Hyg. 82(6), 2010, pp1034-1040. 1 study in Mali: Sagara I, Diallo A, Kone M, Coulibaly M, Diawara SI, Guindo O, Maiga H, Niambele MB, Sissoko M, Dicko A, Djimde A, Doumbo OK. A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Am J Trop Med Hyg. 2008 Nov;79(5):655-61. 1 study in Kenya: Bhatt KM, Samia BM, Bhatt SM, Wasunna KM. Efficacy and safety of an artesunate/mefloquine combination, artequin, in the treatment of uncomplicated P. falciparum malaria in Kenya. East Afr Med J.2006 May;83(5):236-42. 1 study in Cote d’Ivoire: Toure OA, Kouame MG, Didier YJ, Berenger AA, Djerea K, Genevieve GO, Penali LK. Artesunate/mefloquine paediatric formulation vs. artemether/lumefantrine for the treatment of uncomplicated Plasmodium falciparum in Anonkoua kouté, Côte d'Ivoire. Trop Med Int Health. 2011 Mar;16(3):290-7. 1 study in Cameroon, Benin & Cote d’Ivoire: Massougbodji A, Kone M, Kinde-Gazard D, Same-Ekobo A, Cambon N, Mueller EA. A randomized, double-blind study on the efficacy and safety of a practical three-day regimen with artesunate and mefloquine for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. Trans R Soc Trop Med Hyg. 2002 Nov-Dec;96(6):655-9. 1 study in Burkina Faso, Tanzania & Cote d’Ivoire: Rueangweerayut R, Phyo AP, Uthaisin C, Poravuth Y, Binh TQ, Tinto H, PénaliLK, Valecha N, Tien NT, Abdulla S, Borghini-Fuhrer I, Duparc S, Shin CS and Fleckenstein L for the Pyronaridine–Artesunate Study Team. Pyronaridine–Artesunate versus Mefloquine plus Artesunate for Malaria. N Engl J Med. 2012, Apr 5; 366 (14):1298-309. Thailand, Cambodia, Vietnam, Burkina Faso, Tanzania, Cote d’Ivoire & India.


46

Appendix 2 Studies using several commercial brands of either loose or FDC of AS+MQ Table I. Studies performed in Thailand using AS+MQ over 3 days, all PCR corrected

Year/Country/ Location Author Year of Study

Drugs: AS 3 days + MQ 24-25 mg/Kg

Number and age of patients treated with AS+MQ


Comparative studies

199835 Thailand Mae La

van Vugt M 1995-1996 AS (Guilin) +MQ (Hoffman-La Roche) and artemether-benflumetol

N=308 5-66 yr

94%

200036Thailand Bangkok and Mae La

van Vugt M 1997- 1998

AS (Guilin) +MQ (Hoffman-La Roche) and AL

N=50 3-61 yr

100%


Lefevre G 1998-1999 AS (Guilin) +MQ (Hoffman-La Roche) and AL

N=55 >12 yr

100%

200288 Thailand Mae La and Mawker Thai

van Vugt M 1998-2000 AS+MQ, atovaquone-proguanil and atovaquone-proguanil-AS (Manufacturer non specified)

N=533 2-68 yr

97,6%

200389 Thailand Kanchanaburi

Suputtamongkol Y 1999-2001 AS (Guilin) +MQ (Mepha) and MQ-Primaquine

N=320 Children and adults

97,5%


Ashley EA 2002- 2003

AS (Guilin) +MQ (Atlantic), DHA-PQ and DHA-PQ+AS

N=176 1-65 yr

94,9%

200538 Thailand Mae La and Mawker Tai

Hutagalung R 2001- 2002

AS (Guilin) +MQ (Hoffman-La Roche) and AL

N=245 2-72 yr

96,3%


Ashley EA 2003-o 2004

AS (Guilin) +MQ (Atlantic) and DHA-PQ

N=166 1-55 yr

95,7%

200660 Thailand Mae La and 3 clinics in Thai villages

Ashley EA 2004-2005 AS (Sanofi) +MQ (Roche) and ASMQ (Farmanguinhos)

N=250 & 250 6 m-65 yr

89,2% and 91,9%

200990 Thailand Wang Pha

Dondorp AM 2007-2008 AS (Guilin)+MQ (Mepha) and AS

N=20 >16 & adults

95%

201058Thailand Bangkok

Krudsood S 2004-2005 AS (Sanofi) +MQ (Roche) and ASMQ (Farmanguinhos)

N=25 & 25 18-65yr

91,7 % and 100%


47

201049Thailand Bangkok, Ratchaburi and Tak

Valecha N 2005- 2007

AS (Mepha) +MQ (Mepha) and DHA-PQ (Sigma Tau)

N= 234 3m – 65 yr

97%

201256Thailand Mae Sot and Mae Ramat

Rueangweerayut R 2007-2008 AS (Mepha) +MQ (Mepha) and AS-Pyr

N= 88 & 94 3-60 yr

96,6% and 94,7%

Study in pregnant women 2nd & 3rd trimester 200091 Thailand Shoklo and Mae La

McGready R 1995-1997 AS (Guilin) +MQ (Hoffman-La Roche) and Quinine

N=66 15-37yr 2nd and 3rd trimesters

98,2%

Non-comparative studies

201092 Thailand Mae Tao, Tak

Na-Bangchang 2008- 2009

AS (Atlantic) +MQ (Atlantic) +Primaquine

N= 132 16-50 yr

83% at D28 and 72,6% at D42

201093 Thailand Tak

Congpuong K 2008-2009 AS (Atlantic) +MQ(Atlantic) + Primaquine

N=240 4-69 yr

99,2%

Table II. Studies performed in Thailand using AS 4 to 12mg/kg over 3 days + MQ 24-25 mg/Kg over 2 to 3 days, non PCR corrected

Year/ Country/Location


Drugs Number and age of patients treated with AS+MQ

AS+MQ Efficacy results

199719 Thailand Mae Sot, Shoklo

Price RN 1992-1995 AS12 (Guilin) + MQ (Roche)

N= 1967 5-67 yr

89%


Krudsood S 2001 AS4+MQ simultaneous (Mepha) and AS (Mepha) +MQ (Mepha) sequential

N=203 8-63 yr

100% and 99%

200448Thailand Bangkok

Ashley EA 2002- 2003

AS4(Guilin) +MQ (Atlantic), DHA-PQ and DHA-PQ+AS

N=59 >14 yr

100%


Silachamroon U

Not avail. AS4 (Guilin) +MQ (Manufacturer non specified) and AS (Guilin) +MQ (Manufacturer non specified)

N=120 15-63 yr

100% and 99%

200696 Thailand Thai-Myan border (2 sites) Thai-Cbd border (2 sites)

Vijaykadga S 2003 AS4+MQ (Manufacturer non specified) +Primaquine and MQ +Primaquine

N= 196 10-72 yr

96,6 and 93,8 (N= 109) 78,6 (N=44) and 97,7 (N=43)


Krudsood S 2005 AS+MQ (Manufacturer non specified), AS +Piperaquine, DHA-PQ

N=25 13-60 yr

100%


48

and AL 200882 Thailand Bangkok

Tangpukdee N 2006-2007 AS4 +MQ(Manufacturer non specified) and Artemisinin+ Piperaquine +Primaquine

N=65 15-54 yr

100%

201222Thailand Thai-Cbd border,7 provinces: Buriram, Chantaburi, Sakaew, Srisaket, Surin, Trat and Ubon Ratchathani

Satimai W 2009-2011 AS (600mg) +MQ (1250mg) + PQ (30 mg single dose) (Manufacturer non specified)

N= 1174 1-50+ yr

Above 90%

Table III. Studies performed in Thailand using various regimens of AS+MQ over < or > 3 days, non PCR corrected

199497 Thailand Location not specified

Karbwang J Not specified

AS (Atlantic) 200 mg +MQ(Hoffman-La Roche) 750 mg and 500 mg, 6 and 12 hours after AS vs. MQ

N= 12 17-48 yr

66%

199898 Thailand Thai-Myan border

Sabchareon A 1995-1996 AS (6 mg/kg/d/day) vs. AS suppositories (15 mg/kg/d/3 days), both with MQ 25 mg/kg

N= 21 N=24

100% 92%

199899 Thailand Thai-Myan border

Price RN 1993- 1995

MAS5: AS(Guilin), 5 d (12 mg/kg) and MQ(Roche) 25 mg/kg single dose MAS7: AS(Guilin), 7 d (12 mg/kg) and MQ(Roche) 25 mg/kg single dose

N=49 (0.6-56 yr) N=132 (0.6-17 yr)

94% 93%

2003100 Thailand Thai-Myan border: Tak & Kanchanaburi Thai-Camb border: Chanthaburi & Trat

RojanawatsirivejC 2002 AS (Guilin) 12 mg/kg + MQ(Mepha) 25 mg/kg +PQ (2 days) +PQ over 2 days AS (Guilin) 12 mg/kg + MQ(Mepha) 15 mg/kg +PQ over 2 days

N=153 10-74 yr Tak, Chanthaburi & Trat N=46 10-74 yr Kanchanaburi

From 84,6% to 91,9% 86,7%

200696Thailand Thai-Camb border, Kanchanaburi

Vijaykadga S 2003 AS 12mg /kg for 2 days + MQ 15mg/kg single dose+ PQ vs. MQ+PQ (Manufacturer non

N= 58 10-72 yr

94,2%


49

specified) 2009101 Thailand Mae La

Ambler MT

1994- 1997

AS (12mg/kg) 2 mg/kg on D0 to 4 and 1 mg/kg on D5 and 6; MQ 15 mg/kg D7 and 10 mg/ kg D8 VS.AS7 (Manufacturer non specified)

N=46 0.3-5 yr

95,6%

Table IV. Studies performed in Cambodia using AS+MQ over 3 days, all PCR corrected






Non-comparative studies

2006102 Cambodia-Kratie, Kampong Speu, Oddar Meanchey, Battambang, Pailin, Pursat, Preah Vihear and Ratanakiri

Denis MB 2003-2004 (The study data goes from 2001-04 in 9 sites but here is only taken MAS3 data)

AS (Mediplantex) +MQ (PharmaDanica)

N=623 >2yr and adults

90 to 100% at D28 79,3% in Pailin (N=81) at D42

2009103 Cambodia-Kampot (Chumkiri)

Rogers WO 2006-2008 AS (MisionPharma) +MQ (PharmaDanica)

N=150 >1 yr and adults

86,9% at D28 and 81,2% at D 42

Comparative studies

200639 Cambodia-Battambang

Denis MB 2003-2004 AS (Mediplantex)+MQ (PharmaDanica)and AL

N=52 15 -50 yr

92,4%

200750 Cambodia-Oddar Meanchey and Siem Reap

Janssens B 2002-2003 AS (Guilin) +MQ (Mepha) and DHA-PQ

N=195 1-57 yr

97,5%


Dondorp AM 2007-2008 AS (Guilin) +MQ (Medochemie) and AS

N=20 >5 & adults

95%


RueangweerayutR 2007-2008 AS (Mepha) +MQ (Mepha) and AS-Pyr

N= 42 3-60 yr

100%

Cambodian studies with various AS+ MQ treatment regimens

2006102 Cambodia- Kratie, Battambang, Pailin, Pursat, Preah Vihear and Ratanakiri

Denis MB 2001-2002 AS (Mediplantex) +MQ (PharmaDanica) N=100: AS 12 mg/kg and MQ 1000 mg in co-blister packs (A + M4)


94 to100% (N=267) 85,7 in Pailin (N=70) at D28


50

N=237: AS and MQ in co-blister packs per 3 age groups

Table V. Studies performed in Myanmar using AS+MQ over 3 days, all PCR corrected

Comparative studies







Smithuis F 2000 to 2001

AS 12mg/kg +MQ 25mg/kg (Manufacturer non specified) supervised and unsupervised


100 % and 96,1%



AS (Guilin) +MQ (Hoffman-La Roche) and DHA-PQ (both supervised and unsupervised)


99,4 % and 100%


Smithuis F 2008-2009 ASMQ (Farmanguinhos) and AS+MQ (Manufacturer non specified)and AL and DHA-PQ and ASAQ


100% and 98,7%

Comparative study using AS+MQ 25 mg as single dose 2004104 Myanmar Rakhine State


AS+MQ (Manufacturer non specified) AS 4mg/kg + MQ 25mg/Kg single dose, supervised


96,4%

Table VI. Studies performed in Myanmar using AS+MQ 15 mg/kg as single dose, non PCR corrected Year/ Country/Location



AS+MQ Non- PCR corrected



AS+MQ (Manufacturer non specified) AS 4mg/kg + MQ 15mg/Kg single dose, supervised


94,1%

2004105 Myanmar Kachin State

Smithuis F 1998 AS (Guilin) 4 mg/kg +MQ (Manufacturer non specified) 15 mg/kg (single dose) vs. CQ vs. MQ vs. SP

N=76 1-51 yr

79%


51

Table VII. Studies performed in other Asian countries using AS+MQ over 3 days, all PCR corrected Comparative studies







Mayxay M 2002 to 2003

AS (Guilin) +MQ (Roche), CQ+SP and AL


100%

200442 Laos Luang Nahtha

Stohrer JM 2003 AS (Mepha) +MQ (Mepha) and AL

N=53 2-66 yr

100%


Mayxay M 2004 AS (Guilin) +MQ (Roche) and DHA-PQ

N=107 >1 yr and adults

99%


Mayxay M 2005- 2006

AS (Mepha) +MQ (Mepha) and DHA-PQ

N=98 3m – 65 yr

100%

200454 Vietnam Ho Chi Minh and Binh Phuoc

Hien TT 2001 AS (Guilin) +MQ (Hoffmann-La Roche), DHA-TP and DHA-PQ

N=38 & 77 8-56 yr

100% and 98,7%

201256 Vietnam Ho Chi Minh and Hanoi


N=42 & 13 3-60 yr

100% and 100%

200543 Bangladesh, Chittagong Hills

van den Broek IV 2003 AS +MQ (Manufacturer non specified), CQ+SP and AL

N= 121 1.2 m -80 yr

100%

201049India Assam, Goa and Mangalore

Valecha N 2005-2007 AS (Mepha) +MQ (Mepha) and DHA-PQ

N= 49 3m – 65 yr

97%

201256India Mangalore


N= 13 3-60 yr

100%

Table VIII Asian studies with various AS+ MQ regimens, non PCR-corrected




AS+MQ Efficacy results

2004106 Vietnam Binh Thuan

Hung LQ 1997-2001 AS (Mepha) 4 mg/kg +MQ(Mepha) 15 mg/kg simultaneously; AS (Mepha) 4 mg/kg +MQ(Mepha) 15 mg/kg after 8 hs. and AS (Mepha) 4 mg/kg +MQ(Mepha) 15 mg/kg after 24 hs

N=114 9-58 yr N=110 9-58 yr N=113 9-58 yr

74% 74% 67%

2006107 India Assam State

Campbell P 2001 AS 4 mg/kg/3 days + MQ15 mg/kg on day 0 vs. MQ vs. CQ vs. SP

N=60 1-75yr

93,6%


52

(Manufacturer non specified)

Table IX. Studies performed in Africa using several regimens of AS+MQ

African studies PCR corrected





2005108 Sudan New Halfa

Adam I 2003 AS (Dafra Pharma) + MQ (Hoffmann-La Roche) [AS at 4 mg/kg/d for 3D and MQ at 15mg/kg on the 3rd day] and MQ

N=38 <5 and adults

94,7%

200744 Senegal

Richard Toll & Podor (North); Guediawaye & Kaolack (Central) and Velingara (South)

Faye B 2003- 2004 AS (12 mg) + MQ (15mg) for 3D, Artequin™ Mepha, AS+AQ, AL and AQ+SP

N=145 >2-65yr

100%

200845 Mali Kambila

Sagara I 2004-2005 AS+MQ (Artequin™ Mepha) for 3 days (as 3 strengths: AS600/MQ750 for >31kg; AS300/MQ375 for 15-30kg and AS4 & MQ 5 mg/kg for the 10-14 kg) and AL

N=232 >1-70yr

96,04%

2009109 Nigeria Ibadan

Sowunmi A 2007-2008 AS+MQ (AS at 4 mg/kg/d for 3D and MQ at 25mg/kg on day 0) (Manufacturer non specified) and MQ

N= 166 < 10 yr

97%

201026 Senegal Ndoffane and Kaolack

Faye B 2008 AS+MQ (Artequin™ Pediatric Mepha) daily for 3 days at 4 and 8 mg/kg/D and AL

N=154 2-7 yr

100%

2010110 Gabon Libreville and Lambaréné

Bouyou-Akotet MK

2005 -2006 AS+MQ (Artequin™ Pediatric Mepha and Artequin™ Mepha) daily for 3 days at 4 and 8 mg/kg/D

N=39 & 29 1-13 yr

95 and 97%


53

2010111 Cameroon Yaoundé

Whegang SY 2006 AS+MQ (AS at 4 mg/kg/d for 3D and MQ at 15mg/kg on day 1 and 10mg/kg on day 2) (Manufacturer non specified) and AQ-SP

N=61 < 5 y

100%

2010112 Cameroon Yaoundé

Tietche F 2007-2009 AS+MQ (Artequin™ Pediatric Mepha) for 3D: AS 2.5–5 mg/kg/D and MQ 6.25–12.5 mg/kg/D

N=213 8 months-8 yr

96,6%

201146 Côte d’Ivoire Anonkoua Kouté

Toure OA 2007 AS+MQ (co-formulated Mepha) for 3D: AS 50 mg + MQ 127 mg and AL

N=75 6-59 months

99%

201256 Burkina faso, Tanzania & Côte d’Ivoire


N= 76 3-60 yr

100%

African studies in special groups, non PCR-corrected

1998113 Nigeria Ibadan

Sowunmi A 1994 to 1997

Artemether-MQ (Manufacturer non specified) (3,2 mg/kg artemether IM on D0 + MQ 15 mg/kg/d divided among D1 and D2) and artemether.

N=22 2nd and 3rd trimester pregnant women 21-41 yr

100%

African studies non-PCR corrected 2002114 Benin, Cameroon and Côte d’Ivoire

Massougbodji A 2001 AS+MQ(Mepha) simultaneous and sequential

N=104 >6-64yr

100% and 98%

2003115 Sudan Khartoum

Awad MI 2000 to 2001

AS suppositories (Mepha) 200mg every 8 hours/3 days, sequential with MQ (Mepha), 15 mg/kg, 2 doses 24 hs. apart, 12 hs. after AS and AS+doxicycine and AS+SP

N=30 18-65yr Severe Malaria

100%

2006116 Kenya Bungoma

Bhatt KM 2004 AS+MQ (Mepha) daily for 3 days at 4 and 8 mg/kg/d

N=129 >14 and adults

98,4%

2007117 Gabon Lambaréné

Ramharter M 2005 to 2006

ASMQ (co-formulated Mepha) daily for 3 days at 4 and 8 mg/kg/d

N=24 >2,3-12yr

100%

2008118 Nigeria Agomo PU ? AS+MQ (co-formulated N=431 97,45%


54

North-east, north-west, south-east and south-west

Mepha) daily for 3 days: AS at 4mg/kg/d and MQ 25mg/kg total

3-65yr

Table X. Studies performed in Latin America using several regimens of artesunate combined with mefloquine

Latin-American studies PCR corrected

Year/Country Author Year of Study



2003119 Peru Iquitos

Pillai DR 2000 AS+MQ (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg single dose, (Manufacturer non specified) and MQ

N=51 5-50 yr

100%

200755 Peru Iquitos

Grande T 2003-2005

AS (Guilin) +MQ (Hoffman La-Roche) daily for 3 days: AS at 4mg/kg/d and MQ at 8mg/kg/d and DHA-PQ

N=260 5-60 yr

99,6%

201247 Colombia Tumaco

Carrasquilla G 2007-2008

AS+MQ (Mepha) as (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg on D2 and 10 mg/kg on D3) vs. AL

N=53 12-65 yr

100%

Latin-American studies non PCR-corrected AS+ MQ Efficacy results


Marquiño W 2000 AS+MQ (Mepha) as (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg single dose) and MQ

N=61 5-50 yr

100%

2003121 Ecuador Manabí, Pichincha. Esmeraldas, Guayas, Cañar & Los Ríos

Gomez L EA ? AS rectal capsule (Mepha) over 3 days in a total dose of 30mg/kg + oral MQ (Mepha) at 20 mg/kg on D1 AS rectal capsule over 3 days in a total dose of 30mg/kg + oral MQ at 15-17mg/kg total dose on D1 and D3

N=50 1-12 yr N=50 1-12 yr

D28: 96% and D60: 88% D28: 94% and D 60: 80%

2004122 Bolivia Beni & Pando

Avila JC 2001 AS+MQ (Mepha) as (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg single dose)

N=70 5-60 yr

100%


55

and MQ 2009123 Peru Iquitos

Gutman J 2004-2005

AS (Mepha)+MQ (Roche, Mepha & A:C: Pharma) (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg D1 and 10 mg/kg D2)

N= 34 >18 -61 yr

100%


Macedo de Oliveira A

2005- 2006

AS+MQ (A.C. Farma Laboratories) as (AS at 4 mg/kg/d for 3 d and MQ at 15mg/kg for 2 days), observed and non observed

N= 96 and 96 3-78 yr

98,9%

2010125 Colombia Antioquia

Álvarez G 2006-2007

AS+MQ daily for 3 days at 12 and 15 mg/kg/d and AS+MQ+PQ (Manufacturer non specified)

N=25 and 25 1-80 yr

100%

201262 Brazil Juruá valley in the Amazon region

Santelli A 2006-2008

ASMQ (Farmanguinhos) N= 23.845 ≥6 months

>90%


56

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PROPOSAL FOR THE INCLUSION OF ARTESUNATE and … · 3. Name of the organisation(s) consulted and/or supporting the application Médecins Sans Frontières (MSF) Medicines for Malaria

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